Supplementary Tables and Figures for

HDAC and MAPK/ERK Inhibitors Cooperate to Reduce

Viability and Stemness Phenotype in Medulloblastoma

Mariane da Cunha Jaeger 1,2 • Eduarda Chiesa Ghisleni 1 • Paula Schoproni

Cardoso 1 • Marialva Siniglaglia 1,2 • Tiago Falcon 3 • André T. Brunetto 1,2 •

Algemir L. Brunetto 1,2 Caroline Brunetto de Farias 1,2 • Michael D. Taylor 4,5,6,7 •

Carolina Nör 4,5 • Vijay Ramaswamy 4,8 • Rafael Roesler 1,9

1 Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical

Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto

Alegre, RS, Brazil

2 Children’s Cancer Institute, Porto Alegre, RS, Brazil

3 Bioinformatics Core, Experimental Research Center, Clinical Hospital (CPE-

HCPA), Porto Alegre, RS, Brazil

4 The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for

Sick Children, Toronto, ON, Canada

5 Developmental and Stem Cell Biology Program, The Hospital for Sick

Children, Toronto, ON, Canada

6 Department of Laboratory Medicine and Pathobiology, University of Toronto,

Toronto, ON, Canada

7 Division of Neurosurgery, The Hospital for Sick Children, Toronto, ON, Canada 8 Division of Haematology/Oncology, The Hospital for Sick Children, Toronto,

ON, Canada

9 Department of Pharmacology, Institute for Basic Health Sciences, Federal

University of Rio Grande do Sul, Porto Alegre, RS, Brazil

Correspondence: Rafael Roesler

Department of Pharmacology, Institute for Basic Health Sciences, Federal University of

Rio Grande do Sul, Rua Sarmento Leite, 500 (ICBS, Campus Centro/UFRGS), 90050-

170 Porto Alegre,RS, Brazil.

Telephone: +5551 33083183; fax: +5551 33083121.

E-mail: [email protected] Supplementary Figure S1: Balloon plot of significantly enriched KEGG pathways of CD133 correlated genes. # of CGs: number of correlated genes. Large circles indicate higher number of correlated genes. A more darker color indicate a more significant p- value. Neurotrophin signaling pathway ErbB signaling pathway Glioma Chronic myeloid leukemia Ras signaling pathway Insulin signaling pathway Prolactin signaling pathway Hepatocellular carcinoma Non
small cell lung cancer Phospholipase D signaling pathway Renal cell carcinoma Relaxin signaling pathway Focal adhesion Gastric cancer Fc epsilon RI signaling pathway Colorectal cancer Endometrial cancer Natural killer cell mediated cytotoxicity FoxO signaling pathway Proteoglycans in cancer Breast cancer Choline metabolism in cancer Insulin resistance C
type lectin receptor signaling pathway TNF signaling pathway Kaposi's sarcoma
associated herpesvirus infection Hepatitis C Estrogen signaling pathway T cell receptor signaling pathway Epstein
Barr virus infection Pathways in cancer Chemokine signaling pathway Toll
like receptor signaling pathway Prostate cancer MAPK signaling pathway Shigellosis MicroRNAs in cancer Osteoclast differentiation Hepatitis B Chagas disease (American trypanosomiasis) Epithelial cell signaling in Helicobacter pylori infection Apoptosis Fluid shear stress and atherosclerosis Pancreatic cancer Influenza A B cell receptor signaling pathway Non
alcoholic fatty liver disease (NAFLD) mTOR signaling pathway Acute myeloid leukemia AGE
RAGE signaling pathway in diabetic complications Th1 and Th2 cell differentiation IL
17 signaling pathway Th17 cell differentiation Sphingolipid signaling pathway VEGF signaling pathway cAMP signaling pathway Adipocytokine signaling pathway PI3K
Akt signaling pathway Autophagy
animal RIG
I
like receptor signaling pathway Pertussis GnRH signaling pathway Type II diabetes mellitus Toxoplasmosis Herpes simplex infection Bacterial invasion of epithelial cells NOD
like receptor signaling pathway Salmonella infection Progesterone
mediated oocyte maturation Viral carcinogenesis
log10(lowest
p) Melanoma HTLV
I infection Longevity regulating pathway
multiple species 50 Thyroid hormone signaling pathway 40 Jak
STAT signaling pathway AMPK signaling pathway 30 HIF
1 signaling pathway Rap1 signaling pathway 20 Measles 10 Longevity regulating pathway Mitophagy
animal Central carbon metabolism in cancer Small cell lung cancer Bladder cancer # of CGs Human papillomavirus infection Inflammatory mediator regulation of TRP channels 0 Regulation of lipolysis in adipocytes Regulation of actin cytoskeleton 20 Thyroid cancer Cytosolic DNA
sensing pathway 40 Cellular senescence Leishmaniasis 60 Fc gamma R
mediated phagocytosis Wnt signaling pathway Tight junction Long
term depression Long
term potentiation Aldosterone
regulated sodium reabsorption Apoptosis
multiple species Carbohydrate digestion and absorption Gap junction Tuberculosis Cholinergic synapse Axon guidance Oxytocin signaling pathway Dopaminergic synapse Leukocyte transendothelial migration Signaling pathways regulating pluripotency of stem cells Alcoholism Apelin signaling pathway Inflammatory bowel disease (IBD) NF
kappa B signaling pathway Cocaine addiction Amphetamine addiction Phosphatidylinositol signaling system Adrenergic signaling in cardiomyocytes Amoebiasis Retrograde endocannabinoid signaling Glucagon signaling pathway Platelet activation Melanogenesis Cushing's syndrome Serotonergic synapse Vascular smooth muscle contraction Prion diseases Inositol phosphate metabolism Protein processing in endoplasmic reticulum cGMP
PKG signaling pathway Transcriptional misregulation in cancer Amyotrophic lateral sclerosis (ALS) Legionellosis Adherens junction Cell cycle Oocyte meiosis Circadian entrainment Aldosterone synthesis and secretion Hippo signaling pathway Parathyroid hormone synthesis, secretion and action Necroptosis Pathogenic Escherichia coli infection p53 signaling pathway Thermogenesis Basal cell carcinoma Gastric acid secretion Calcium signaling pathway Insulin secretion Endocytosis Alzheimer's disease Vibrio cholerae infection Hedgehog signaling pathway Vasopressin
regulated water reabsorption TGF
beta signaling pathway Pancreatic secretion Viral myocarditis Rheumatoid arthritis Ubiquitin mediated proteolysis Huntington's disease Notch signaling pathway Glutamatergic synapse Olfactory transduction Asthma 50 100 150 200 Fold Enrichment Supplementary Figure S2: Balloon plot of significantly enriched KEGG pathways of BMI1 correlated genes. # of CGs: number of correlated genes. Large circles indicate higher number of correlated genes. A more darker color indicate a more significant p- value.

MAPK signaling pathway Hepatitis B Epstein
Barr virus infection GnRH signaling pathway Proteoglycans in cancer TNF signaling pathway Ras signaling pathway Neurotrophin signaling pathway Osteoclast differentiation C
type lectin receptor signaling pathway Toll
like receptor signaling pathway Toxoplasmosis Hepatitis C Pathways in cancer Kaposi's sarcoma
associated herpesvirus infection T cell receptor signaling pathway Pancreatic cancer Relaxin signaling pathway IL
17 signaling pathway Fluid shear stress and atherosclerosis Choline metabolism in cancer Glioma FoxO signaling pathway Estrogen signaling pathway ErbB signaling pathway Colorectal cancer Herpes simplex infection Th1 and Th2 cell differentiation HTLV
I infection Prostate cancer Fc epsilon RI signaling pathway Th17 cell differentiation NF
kappa B signaling pathway PI3K
Akt signaling pathway Epithelial cell signaling in Helicobacter pylori infection Breast cancer NOD
like receptor signaling pathway Bladder cancer Regulation of actin cytoskeleton Melanoma RIG
I
like receptor signaling pathway Rap1 signaling pathway B cell receptor signaling pathway Chagas disease (American trypanosomiasis) Apoptosis Gastric cancer Non
small cell lung cancer AGE
RAGE signaling pathway in diabetic complications Chronic myeloid leukemia Prolactin signaling pathway Shigellosis Focal adhesion mTOR signaling pathway Influenza A Small cell lung cancer Chemokine signaling pathway Pertussis Gap junction Endometrial cancer Phospholipase D signaling pathway Salmonella infection VEGF signaling pathway Acute myeloid leukemia Leishmaniasis Cellular senescence Central carbon metabolism in cancer Progesterone
mediated oocyte maturation Adipocytokine signaling pathway Long
term potentiation Parathyroid hormone synthesis, secretion and action cAMP signaling pathway Sphingolipid signaling pathway Renal cell carcinoma Autophagy
animal Measles Wnt signaling pathway Human papillomavirus infection Thyroid hormone signaling pathway Longevity regulating pathway
multiple species Hepatocellular carcinoma Viral carcinogenesis # of CGs Thyroid cancer Tuberculosis 0 Dopaminergic synapse Insulin signaling pathway 50 Natural killer cell mediated cytotoxicity Jak
STAT signaling pathway 100 Mitophagy
animal Apelin signaling pathway 150 Non
alcoholic fatty liver disease (NAFLD) Adrenergic signaling in cardiomyocytes MicroRNAs in cancer
log10(lowest
p) Retrograde endocannabinoid signaling p53 signaling pathway Inflammatory mediator regulation of TRP channels Longevity regulating pathway 60 cGMP
PKG signaling pathway Oxytocin signaling pathway 40 HIF
1 signaling pathway Long
term depression 20 Insulin resistance Cushing's syndrome Adherens junction Endocytosis Cytosolic DNA
sensing pathway Cocaine addiction Protein processing in endoplasmic reticulum Type II diabetes mellitus Legionellosis Signaling pathways regulating pluripotency of stem cells Amyotrophic lateral sclerosis (ALS) Amphetamine addiction Tight junction Vascular smooth muscle contraction Serotonergic synapse Transcriptional misregulation in cancer Basal cell carcinoma Fc gamma R
mediated phagocytosis Amoebiasis Cholinergic synapse Alcoholism Apoptosis
multiple species Cell cycle Leukocyte transendothelial migration Inflammatory bowel disease (IBD) Platelet activation Melanogenesis Axon guidance Antigen processing and presentation Thyroid hormone synthesis Thermogenesis Insulin secretion Morphine addiction Prion diseases Circadian entrainment Aldosterone synthesis and secretion Calcium signaling pathway Endocrine and other factor
regulated calcium reabsorption Glucagon signaling pathway Regulation of lipolysis in adipocytes Oocyte meiosis Viral myocarditis Hedgehog signaling pathway Alzheimer's disease Gastric acid secretion Carbohydrate digestion and absorption GABAergic synapse Cortisol synthesis and secretion Salivary secretion Glutamatergic synapse Spliceosome Rheumatoid arthritis Aldosterone
regulated sodium reabsorption Necroptosis Dilated cardiomyopathy (DCM) TGF
beta signaling pathway Primary immunodeficiency Arrhythmogenic right ventricular cardiomyopathy (ARVC) Vibrio cholerae infection Cardiac muscle contraction Hypertrophic cardiomyopathy (HCM) Hippo signaling pathway
multiple species Ovarian steroidogenesis Ubiquitin mediated proteolysis Hippo signaling pathway AMPK signaling pathway African trypanosomiasis Bacterial invasion of epithelial cells Graft
versus
host disease Vasopressin
regulated water reabsorption Type I diabetes mellitus Renin secretion Cytokine
cytokine receptor interaction Bile secretion Pancreatic secretion Taste transduction Malaria Pathogenic Escherichia coli infection Huntington's disease Phagosome Parkinson's disease Non
homologous end
joining 40 80 120 Fold Enrichment Supplementary Table S1: Enrichment analysis (KEGG pathways) of CD133 correlated genes.

ID Pathway Fold_Enric occurre lowest_p highest_ Positively_corr Negatively_corr hment nce p elated elated hsa04722 Neurotrophin 128.38596 10 2E-60 1.9E-49 PIK3CB, NTRK3, signaling PIK3R1, PIK3CA, pathway PLCG2, PIK3R2, SHC1, SHC2, PLCG1, SHC4, HRAS, GRB2, NGF, MAP2K2, NGFR, AKT1, RPS6KA1, AKT3, BRAF, CRK, FOXO3, SOS1, SOS2, NFKBIA, MAPK3, NFKBIB, RAPGEF1, ATF4, SORT1, RAP1B, CAMK4, PTPN11, CAMK2A, GAB1, GSK3B, CAMK2D, NFKBIE, CAMK2G, NFKB1, RELA, MATK, RHOA, FRS2, PDPK1, TP53, KIDINS220, MAP3K1, RPS6KA5, JUN, IRS1, MAPK8, MAPKAPK2, MAPK9, MAP2K5, MAPK10, ARHGDIG, MAPK11, SH2B3, MAPK7, MAP2K7, ARHGDIA, PRDM4, SH2B2, RIPK2, IRAK4, SH2B1, ABL1, YWHAE, CDC42, RAC1, IKBKB, TP73, PSEN2, BAX MAGED1, IRAK2, CALM3 hsa04012 ErbB 133.84545 10 6.1E-39 7.3E-33 MAP2K7, GRB2, GSK3B, signaling CRK, SHC1, GAB1, MAPK8, pathway SHC2, MAPK9, CAMK2A, MAPK10, CAMK2D, SOS1, SOS2, CAMK2G, SHC4, PLCG1, PLCG2, JUN, ABL1, PIK3CA, PIK3CB, PIK3R2, AKT1, PIK3R1, AKT3, MAPK3, MAP2K2, BRAF HRAS hsa05214 Glioma 127.54684 10 8.3E-30 2.4E-27 CAMK2A, CALM3, SHC4, CAMK2D, GRB2, SOS1, CAMK2G, SOS2, BRAF, SHC1, SHC2, MAPK3, MAP2K2, PIK3CA, PIK3CB, PIK3R2, AKT1, PIK3R1, TP53, AKT3, PLCG1 PLCG2, HRAS, BAX ID Pathway Fold_Enric occurre lowest_p highest_ Positively_corr Negatively_corr hment nce p elated elated hsa05220 Chronic 114.12086 10 2.1E-29 4.8E-26 TP53, PTPN11, ABL1, myeloid NFKBIA, NFKB1, RELA, leukemia IKBKB, SHC1, SOS1, SOS2, SHC2, CRK, GRB2, SHC4, PIK3CB, AKT1, AKT3, PIK3R1, PIK3CA, MAP2K2, PIK3R2, HRAS, BAX MAPK3, BRAF hsa04014 Ras signaling 52.017209 10 1.1E-27 3.8E-27 MAP2K2, MAPK3, GRB2, pathway HRAS, SOS1, SOS2, PIK3CB, AKT1, AKT3, PIK3R1, PIK3CA, SHC1, SHC2, PIK3R2, SHC4, IKBKB, RHOA, NGF, NGFR, PLCG2 GAB1, PTPN11, RAC1, ABL1, NFKB1, RELA, MAPK8, MAPK9, MAPK10, CDC42, RAP1B, CALM3, PLCG1 hsa04910 Insulin 73.722074 10 1.8E-27 1.2E-24 IKBKB, HRAS, MAPK8, signaling MAP2K2, MAPK9, pathway SHC1, SHC2, MAPK10, PIK3CB, MAPK3, PIK3R1, CRK, CALM3, SOS1, IRS1 SOS2, SHC4, GRB2, BRAF, AKT1, AKT3, PIK3CA, PIK3R2, GSK3B, RAPGEF1, SH2B2, PDPK1 hsa04917 Prolactin 109.98604 10 1.6E-26 6E-23 PIK3CB, AKT1, AKT3, signaling PIK3R1, PIK3CA, pathway MAP2K2, PIK3R2, HRAS, SHC1, MAPK3, SHC4, SHC2, FOXO3 GRB2, SOS1, SOS2, MAPK8, MAPK9, MAPK10, MAPK11, GSK3B, NFKB1, RELA ID Pathway Fold_Enric occurre lowest_p highest_ Positively_corr Negatively_corr hment nce p elated elated hsa05225 Hepatocellula 60.626706 10 5.9E-26 2.1E-23 HRAS, BRAF, MAPK3, r carcinoma MAP2K2, SHC4, GRB2, SHC1, SHC2, SOS1, SOS2, PIK3CB, PIK3CA, PIK3R1, TP53, PIK3R2, AKT1, BAX, PLCG2 AKT3, GSK3B, PLCG1, GAB1 hsa05223 Non-small 114.98541 10 2.5E-25 3.2E-23 FOXO3, AKT1, AKT3, cell lung PIK3CB, PDPK1, cancer PIK3R1, PIK3CA, HRAS, PIK3R2, PLCG2, PLCG1, SOS1, MAP2K2, SOS2, GRB2, TP53, BAX MAPK3, BRAF hsa04072 Phospholipas 71.679216 10 8E-25 2.6E-24 MAP2K2, MAPK3, GRB2, e D signaling HRAS, SOS1, SOS2, pathway PIK3CB, AKT1, AKT3, PIK3R1, PIK3CA, SHC1, SHC2, PIK3R2, SHC4, RHOA, GAB1, PLCG2 PTPN11, PLCG1 hsa05211 Renal cell 108.41481 10 5.4E-23 2.4E-17 CRK, PIK3CB, PTPN11, carcinoma PIK3R1, JUN, RAC1, MAP2K2, RAPGEF1, HRAS SOS1, SOS2, GRB2, GAB1, RAP1B, CDC42, AKT1, AKT3, PIK3CA, PIK3R2, MAPK3, BRAF hsa04926 Relaxin 65.422733 10 8.1E-23 3.4E-21 NFKBIA, AKT1, AKT3, signaling PIK3CB, NFKB1, RELA, pathway PIK3R1, MAPK3, ATF4, HRAS, PIK3CA, MAP2K2, PIK3R2, SHC4, SHC1, SHC2, SOS1, SOS2, JUN, MAP2K7 MAPK11, MAPK8, MAPK9, MAPK10, GRB2 ID Pathway Fold_Enric occurre lowest_p highest_ Positively_corr Negatively_corr hment nce p elated elated hsa04510 Focal 48.725759 10 9.3E-23 2.5E-20 PIK3CB, CDC42, AKT1, adhesion PIK3R1, AKT3, PDPK1, RHOA, HRAS, PIK3CA, SHC1, SHC2, PIK3R2, CRK, JUN MAPK3, BRAF, SOS1, SOS2, GRB2, SHC4, RAPGEF1, RAP1B, MAPK8, MAPK9, MAPK10, RAC1, GSK3B hsa05226 Gastric 63.031869 10 1.1E-22 5.4E-20 HRAS, BRAF, MAPK3, cancer MAP2K2, SHC4, GRB2, SHC1, SHC2, SOS1, SOS2, PIK3CB, PIK3CA, PIK3R1, TP53, PIK3R2, AKT1, BAX AKT3, GSK3B, GAB1 hsa04664 Fc epsilon RI 103.2522 10 6E-22 1E-20 MAP2K7, AKT1, AKT3, signaling PIK3CB, MAPK11, pathway PIK3R1, PDPK1, PLCG2, PIK3CA, MAP2K2, PIK3R2, HRAS PLCG1, MAPK3, SOS1, SOS2, GRB2, MAPK8, MAPK9, MAPK10, RAC1 hsa05210 Colorectal 82.905447 10 8.6E-22 1.4E-19 PIK3CB, PIK3CA, cancer PIK3R1, PIK3R2, BRAF, RHOA, MAPK8, MAP2K2, MAPK9, JUN, TP53, MAPK10, BAX, HRAS RAC1, MAPK3, GSK3B, AKT1, AKT3, SOS1, SOS2, GRB2 hsa05213 Endometrial 114.12086 10 1.6E-21 1.9E-19 HRAS, GSK3B, cancer FOXO3, PDPK1, SOS1, PIK3CB, SOS2, GRB2, PIK3R1, AKT1, AKT3, MAP2K2, PIK3CA, TP53, BAX PIK3R2, MAPK3, BRAF ID Pathway Fold_Enric occurre lowest_p highest_ Positively_corr Negatively_corr hment nce p elated elated hsa04650 Natural killer 65.991626 10 2.3E-21 2.5E-19 PLCG2, PLCG1, cell mediated PIK3CB, PTPN11, cytotoxicity PIK3R1, PIK3CA, MAP2K2, PIK3R2, HRAS, SHC1, MAPK3, BRAF, SHC2 SOS1, SOS2, GRB2, SHC4, RAC1 hsa04068 FoxO 59.756197 10 3.5E-21 2.1E-19 IKBKB, MAPK8, signaling FOXO3, MAPK9, pathway HRAS, MAPK10, MAP2K2, MAPK3, SOS1, PIK3CB, SOS2, BRAF, PIK3R1, IRS1 AKT1, AKT3, PIK3CA, PIK3R2, PDPK1, GRB2, MAPK11 hsa05205 Proteoglycan 43.951952 10 8.2E-21 2.7E-18 RHOA, PIK3CA, s in cancer PIK3CB, PIK3R2, AKT1, PIK3R1, AKT3, GAB1, CAMK2A, RAC1, CDC42, CAMK2D, BRAF, MAPK3, CAMK2G, GRB2, PDPK1, HRAS, FRS2, MAP2K2, PTPN11, TP53, PLCG2 SOS1, SOS2, PLCG1, MAPK11 hsa05224 Breast cancer 59.289352 10 8.3E-21 8.3E-19 HRAS, BRAF, MAPK3, MAP2K2, SHC4, GRB2, SHC1, SHC2, SOS1, SOS2, JUN, PIK3CB, PIK3CA, PIK3R1, TP53, PIK3R2, AKT1, BAX AKT3, GSK3B hsa05231 Choline 82.340366 10 4.8E-20 1.1E-18 HRAS, MAPK8, metabolism in MAP2K2, MAPK9, cancer PIK3CB, MAPK10, PIK3R1, JUN MAPK3, SOS1, SOS2, AKT1, AKT3, PIK3CA, PIK3R2, PDPK1, GRB2, PLCG1, RAC1 hsa04931 Insulin 94.324382 10 9.5E-20 9.5E-20 IKBKB, IRS1, MAPK8, resistance PIK3CB, MAPK9, PIK3R1, MAPK10, NFKBIA, PIK3CA, RPS6KA1 PIK3R2, GSK3B, NFKB1, RELA, PTPN11, PDPK1, AKT1, AKT3 ID Pathway Fold_Enric occurre lowest_p highest_ Positively_corr Negatively_corr hment nce p elated elated hsa04625 C-type lectin 115.40932 10 2.9E-19 4.9E-16 HRAS, IKBKB, NFKB1, RELA, receptor RHOA, PTPN11, signaling MAPKAPK2, MAPK3, pathway NFKBIA, PIK3CA, PLCG2, PIK3R2, AKT1, PIK3CB, AKT3, CALM3, PIK3R1, JUN MAPK11, MAPK8, MAPK9, MAPK10 hsa04668 TNF signaling 103.20256 10 3E-19 4.9E-14 MAP2K7, MAPK11, pathway IKBKB, MAPK8, NFKBIA, MAPK9, ATF4, JUN, MAPK10, PIK3CB, NFKB1, RELA, PIK3R1 MAPK3, RPS6KA5, PIK3CA, PIK3R2, AKT1, AKT3 hsa05167 Kaposi's 67.680925 10 4.4E-19 2.3E-17 IKBKB, MAPK8, sarcoma- NFKBIA, MAPK9, associated PIK3CB, MAPK10, herpesvirus PIK3R1, BAX, AKT1, AKT3, infection TP53, HRAS, PIK3CA, MAP2K2, PIK3R2, JUN, PLCG2, NFKB1, RELA, MAPKAPK2, GSK3B, MAP2K7 PLCG1, MAPK3, RAC1, MAPK11, CALM3 hsa05160 Hepatitis C 78.337199 10 6E-19 6E-19 NFKBIA, NFKB1, RELA, IKBKB, HRAS, MAPK3, GRB2, PIK3CB, SOS1, SOS2, PIK3R1, TP53, BRAF, MAP2K2, PIK3CA, YWHAE, BAX PIK3R2, AKT1, AKT3, GSK3B hsa04915 Estrogen 59.135354 10 2.3E-18 4.8E-17 JUN, HRAS, MAPK3, signaling MAP2K2, PIK3CA, pathway ATF4, PIK3R2, AKT1, PIK3CB, AKT3, SHC4, PIK3R1, GRB2, SOS1, SHC1, SHC2 SOS2, CALM3 hsa04660 T cell 89.19446 10 3.2E-18 3.2E-18 NFKBIA, NFKBIE, receptor NFKBIB, NFKB1, RELA, signaling IKBKB, AKT1, AKT3, pathway PIK3CB, PDPK1, GRB2, PIK3R1, PIK3CA, HRAS, JUN, PIK3R2, SOS1, RHOA, SOS2, PLCG1, MAP2K2, CDC42, MAP2K7 MAPK3, MAPK9, MAPK11, GSK3B ID Pathway Fold_Enric occurre lowest_p highest_ Positively_corr Negatively_corr hment nce p elated elated hsa05169 Epstein-Barr 48.144737 10 4.5E-18 5E-17 TP53, NFKBIE, virus infection NFKBIA, NFKB1, RELA, NFKBIB, MAPK8, MAP2K7, MAPK9, JUN, PIK3CB, MAPK10, PIK3R1, MAPK11, PLCG2, BAX, PIK3CA, IRAK4, IKBKB PIK3R2, AKT1, AKT3, RAC1 hsa05200 Pathways in 19.565306 10 6.9E-18 3.1E-16 CRK, PIK3CB, ABL1, PIK3CA, cancer PIK3R1, PIK3R2, IKBKB, HRAS, GSK3B, GRB2, MAP2K2, SOS1, SOS2, NFKBIA, BRAF, NFKB1, PLCG2, RELA, PLCG1, RHOA, JUN, RAC1, MAPK8, TP53, BAX, MAPK9, CAMK2A, MAPK10, CAMK2D, CDC42, CAMK2G MAPK3, AKT1, AKT3, RPS6KA5, CALM3 hsa04062 Chemokine 45.7595 10 3.1E-17 6.5E-15 RHOA, PIK3CA, signaling PIK3CB, PIK3R2, SHC4, pathway PIK3R1, GRB2, CDC42, SHC1, SHC2, RAP1B, CRK, HRAS, MAPK3, AKT1, IKBKB, AKT3, BRAF, NFKBIA, RAC1, NFKB1, NFKBIB, RELA, SOS1, FOXO3 SOS2, GSK3B hsa04620 Toll-like 106.05797 10 3.9E-17 3.9E-14 IRAK4, IKBKB, MAPK3, receptor NFKBIA, NFKB1, signaling PIK3CB, MAPK11, pathway PIK3R1, RAC1, MAPK8, MAP2K7, MAPK9, MAP2K2, JUN MAPK10, AKT1, AKT3, PIK3CA, PIK3R2, RELA hsa05215 Prostate 64.813205 10 5.3E-17 2.8E-16 NFKBIA, NFKB1, RELA, cancer HRAS, TP53, PDPK1, SOS1, IKBKB, ATF4, SOS2, GRB2, PIK3CB, GSK3B, AKT1, PIK3R1, AKT3, PIK3CA, MAP2K2 PIK3R2, MAPK3, BRAF ID Pathway Fold_Enric occurre lowest_p highest_ Positively_corr Negatively_corr hment nce p elated elated hsa04010 MAPK 44.351515 10 5.9E-17 2.1E-13 IKBKB, NFKB1, RELA, signaling MAP2K2, MAPK3, BRAF, pathway HRAS, RAP1B, SOS1, MAP2K5, SOS2, GRB2, MAPKAPK2, NGFR, ATF4, TP53, MAPK7, MAP2K7, RPS6KA5, CRK, JUN, MAPK11, MAP3K1, AKT1, AKT3, RPS6KA1, CDC42, RAC1, IRAK4 MAPK8, MAPK9, MAPK10, NGF hsa05131 Shigellosis 104.31932 10 9.5E-17 6.1E-12 CRK, RIPK2, RAC1, ABL1, IKBKB, CDC42, NFKBIA, NFKB1, RELA, NFKBIB MAPK8, MAPK9, MAPK10, MAPK3, MAPK11 hsa05206 MicroRNAs in 53.070189 10 1.5E-16 4.3E-16 CRK, HRAS, ABL1, PIK3R2, cancer IRS1, RHOA, MAPK7, IKBKB, TP53, PIK3CA, PLCG2, NFKB1, GRB2, MAP2K2, RPS6KA5, SHC1 PLCG1, SOS1, SOS2, SHC4 hsa04380 Osteoclast 83.396011 10 1.9E-16 1.8E-13 IKBKB, NFKB1, RELA, differentiation NFKBIA, MAPK8, PIK3CB, MAPK9, PIK3R1, JUN, MAPK10, PLCG2, MAPK11, CAMK4, PIK3CA, MAP2K7 PIK3R2, AKT1, AKT3, GRB2, MAPK3, RAC1 hsa05161 Hepatitis B 50.723377 10 2.8E-16 5.2E-13 BAX, MAPK3, MAP2K2, NFKB1, RELA, ATF4, HRAS, GRB2, MAPK8, MAP3K1, MAPK9, NFKBIA, JUN, MAPK10, TP53, PIK3CA, PIK3CB, PIK3R2, AKT1, PIK3R1, AKT3 IKBKB hsa05142 Chagas 92.437895 10 3.7E-16 3.4E-14 IRAK4, JUN, MAPK8, disease NFKBIA, MAPK9, (American IKBKB, MAPK10, trypanosomia PIK3CB, MAPK11, sis) PIK3R1 MAPK3, NFKB1, RELA, PIK3CA, PIK3R2, AKT1, AKT3 ID Pathway Fold_Enric occurre lowest_p highest_ Positively_corr Negatively_corr hment nce p elated elated hsa05120 Epithelial cell 120.09026 10 2E-15 2.6E-12 JUN, IKBKB, MAPK11, signaling in NFKBIA, MAPK8, Helicobacter PLCG2 MAPK9, pylori MAPK10, infection NFKB1, RELA, CDC42, RAC1, PLCG1, PTPN11 hsa04210 Apoptosis 59.255061 10 2.5E-15 6.4E-15 TP53, NFKB1, RELA, NFKBIA, AKT1, AKT3, IKBKB, PIK3CA, PIK3CB, PIK3R2, NGF, PIK3R1, BAX, MAPK8, JUN, ATF4, MAPK9, HRAS, MAPK10, MAP2K2 PDPK1, MAPK3 hsa05418 Fluid shear 67.035115 10 2.5E-15 9.9E-12 JUN, PIK3CB, MAPK11, stress and PIK3R1, AKT1, AKT3, atheroscleros MAP2K7, MAPK8, is MAP2K5, MAPK9, RHOA, TP53, MAPK10, IKBKB PIK3CA, PIK3R2, MAPK7, RAC1, NFKB1, RELA, CALM3 hsa05212 Pancreatic 92.437895 10 2.6E-15 2.6E-15 PIK3CB, PIK3CA, cancer PIK3R1, PIK3R2, AKT1, IKBKB, TP53, AKT3, RAC1, BAX NFKB1, RELA, BRAF, MAPK3, MAPK8, MAPK9, MAPK10, CDC42 hsa05164 Influenza A 61.366876 10 3.8E-15 4.4E-14 IKBKB, JUN, NFKB1, RELA, NFKBIA, PIK3CA, NFKBIB, PIK3R2, AKT1, PIK3CB, AKT3, PIK3R1, MAPK11, IRAK4, MAPK8, MAP2K7, MAPK9, MAP2K2 MAPK10, GSK3B, MAPK3 hsa04662 B cell 141.41063 10 4.6E-15 4E-14 NFKBIA, NFKBIE, receptor NFKBIB, NFKB1, RELA, signaling IKBKB, GSK3B, AKT1, pathway PIK3CB, AKT3, PIK3CA, PIK3R1, JUN, PIK3R2, RAC1, HRAS, MAPK3, SOS1, PLCG2, SOS2, GRB2 MAP2K2 ID Pathway Fold_Enric occurre lowest_p highest_ Positively_corr Negatively_corr hment nce p elated elated hsa04932 Non-alcoholic 57.91848 10 1.3E-14 1.3E-14 IRS1, PIK3CB, AKT1, AKT3, fatty liver PIK3R1, BAX, NFKB1, RELA, disease ATF4, JUN, PIK3CA, (NAFLD) IKBKB PIK3R2, GSK3B, MAPK8, MAPK9, MAPK10, CDC42, RAC1 hsa04150 mTOR 57.060429 10 1.3E-14 1.3E-14 IRS1, PIK3CB, PIK3CA, signaling PIK3R1, PIK3R2, BRAF, pathway HRAS, MAPK3, MAP2K2, PDPK1, AKT1, RHOA, AKT3, GRB2, RPS6KA1, SOS1, SOS2, IKBKB GSK3B hsa05221 Acute 76.229167 10 1.4E-14 1.6E-12 HRAS, IKBKB, NFKB1, RELA, myeloid PIK3CB, SOS1, SOS2, leukemia PIK3R1, GRB2, AKT1, MAP2K2 AKT3, PIK3CA, PIK3R2, MAPK3, BRAF hsa04933 AGE-RAGE 127.26957 10 1.6E-14 1.9E-12 HRAS, JUN, NFKB1, RELA, signaling BAX, PIK3CB, MAPK8, pathway in PIK3R1, MAPK9, diabetic PLCG2 MAPK10, complications MAPK11, MAPK3, AKT1, AKT3, PIK3CA, PIK3R2, CDC42, RAC1, PLCG1 hsa04658 Th1 and Th2 114.79216 10 1.7E-14 3.7E-10 NFKBIA, NFKBIE, cell NFKBIB, NFKB1, RELA, differentiation IKBKB, JUN MAPK3, MAPK11, MAPK8, MAPK9, MAPK10, PLCG1 hsa04657 IL-17 72.495322 10 1.8E-14 1.1E-11 IKBKB, NFKB1, RELA, signaling NFKBIA, JUN MAPK3, pathway MAPK7, MAPK8, MAPK11, MAPK9, MAPK10, GSK3B hsa04659 Th17 cell 97.573333 10 5.1E-14 5E-10 NFKBIA, NFKBIE, differentiation NFKBIB, NFKB1, RELA, IKBKB, JUN MAPK3, MAPK11, MAPK8, MAPK9, MAPK10, PLCG1 ID Pathway Fold_Enric occurre lowest_p highest_ Positively_corr Negatively_corr hment nce p elated elated hsa04071 Sphingolipid 61.625263 10 1.1E-13 7.3E-12 MAP2K2, MAPK3, AKT1, signaling PIK3CB, AKT3, PIK3CA, pathway PIK3R1, PIK3R2, HRAS, RHOA, PDPK1, BAX, TP53 MAPK8, MAPK9, MAPK10, MAPK11, NFKB1, RELA, RAC1 hsa04370 VEGF 78.847138 10 1.3E-13 8.4E-13 PLCG2, CDC42, signaling MAPKAPK2, PLCG1, AKT1, pathway PIK3CB, AKT3, PIK3CA, PIK3R1, PIK3R2, SHC2, MAPK11, MAP2K2, MAPK3, RAC1 HRAS hsa04024 cAMP 48.144737 10 1.5E-13 1.5E-13 PIK3CB, PIK3CA, signaling PIK3R1, PIK3R2, AKT1, pathway MAP2K2, AKT3, MAPK3, RHOA, CALM3, CAMK4, RAP1B, BRAF, CAMK2A, MAPK8, CAMK2D, MAPK9, CAMK2G, MAPK10, NFKBIA, JUN NFKB1, RELA, RAC1 hsa04920 Adipocytokin 125.90108 10 1.6E-13 8.4E-12 NFKBIA, NFKB1, RELA, e signaling NFKBIB, NFKBIE, pathway IKBKB, IRS1 PTPN11, MAPK8, MAPK9, MAPK10, AKT1, AKT3 hsa04151 PI3K-Akt 27.071801 10 1.6E-13 7.5E-13 PIK3CB, AKT1, AKT3, signaling PIK3R1, IRS1, PDPK1, pathway FOXO3, TP53, PIK3CA, IKBKB, PIK3R2, YWHAE, NGFR, GSK3B, HRAS, NFKB1, RELA, MAP2K2, NGF, GRB2, ATF4 SOS1, SOS2, MAPK3, RAC1 hsa04140 Autophagy - 56.36457 10 1.9E-13 1.9E-13 IRS1, PIK3CB, PIK3CA, animal PIK3R1, PIK3R2, HRAS, PDPK1, AKT1, MAP2K2 AKT3, MAPK3, MAPK8, MAPK9, MAPK10 hsa04622 RIG-I-like 108.41481 10 4.5E-13 8.3E-11 IKBKB, NFKB1, RELA, receptor NFKBIA, MAPK8, signaling NFKBIB, MAPK9, pathway MAP3K1 MAPK10, MAPK11 ID Pathway Fold_Enric occurre lowest_p highest_ Positively_corr Negatively_corr hment nce p elated elated hsa05133 Pertussis 84.846377 10 7.6E-13 5E-08 RHOA, JUN, CALM3, IRAK4 NFKB1, RELA, MAPK11, MAPK3, MAPK8, MAPK9, MAPK10 hsa04912 GnRH 110.04511 10 7.7E-13 2.5E-10 ATF4, CDC42, signaling CAMK2A, MAPK11, pathway CAMK2D, MAPK7, CAMK2G, CALM3, MAP3K1, MAPK3, SOS1, MAP2K2, SOS2, GRB2, HRAS, MAPK8, MAP2K7, JUN MAPK9, MAPK10 hsa04930 Type II 122.55024 10 7.9E-13 7.9E-13 PIK3CB, PIK3CA, diabetes PIK3R1, IRS1, PIK3R2, mellitus IKBKB MAPK3, MAPK8, MAPK9, MAPK10 hsa05145 Toxoplasmosi 73.640252 10 1E-12 3.5E-10 IRAK4, IKBKB, NFKB1, RELA, s NFKBIA, MAPK3, NFKBIB MAPK8, MAPK9, MAPK10, MAPK11, PDPK1, AKT1, AKT3 hsa05168 Herpes 56.400771 10 1.2E-12 2.3E-09 JUN, NFKBIA, MAPK8, simplex NFKBIB, MAPK9, infection TP53, IKBKB MAPK10, NFKB1, RELA, PTPN11 hsa05100 Bacterial 58.602603 10 1.2E-12 5.1E-12 CRK, PIK3CB, RAC1, CDC42, invasion of PIK3R1, PIK3CA, epithelial cells SHC1, SHC2, PIK3R2, GAB1, RHOA SHC4 hsa04621 NOD-like 52.742342 10 1.5E-12 2.2E-09 RIPK2, IKBKB, MAPK8, receptor JUN, IRAK4, MAPK9, signaling RHOA, MAPK10, pathway NFKBIA, MAPK3, NFKBIB MAPK11, NFKB1, RELA hsa05132 Salmonella 74.106329 10 1.7E-12 8.7E-08 JUN RAC1, CDC42, infection NFKB1, RELA, MAPK8, MAPK9, MAPK10, MAPK3, MAPK11 ID Pathway Fold_Enric occurre lowest_p highest_ Positively_corr Negatively_corr hment nce p elated elated hsa04914 Progesterone 79.006748 10 1.9E-12 1.9E-12 PIK3CB, PIK3CA, -mediated PIK3R1, PIK3R2, AKT1, oocyte RPS6KA1 AKT3, MAPK3, maturation MAPK8, MAPK11, MAPK9, MAPK10, BRAF hsa05203 Viral 65.412291 10 2.6E-12 2.1E-09 TP53, JUN, MAPK3, carcinogenesi BAX, ATF4, PIK3CA, s PIK3CB, PIK3R2, PIK3R1, NFKB1, RELA, HRAS, CDC42, RAC1, YWHAE, GRB2 RHOA, NFKBIA, MAPKAPK2 hsa05218 Melanoma 65.705948 10 3E-12 2.1E-10 TP53, BRAF, AKT1, PIK3CB, AKT3, PIK3CA, PIK3R1, PIK3R2, MAP2K2, MAPK3 HRAS, BAX hsa05166 HTLV-I 29.501456 10 3.4E-12 6.4E-11 HRAS, ATF4, NFKB1, RELA, infection NFKBIA, MAPK8, IKBKB, MAPK9, MAP3K1, MAPK10, JUN, PIK3CB, PIK3CA, PIK3R1, BAX, PIK3R2, AKT1, MAP2K2, AKT3, MAPK3 TP53 hsa04213 Longevity 94.600185 10 6.5E-12 6.5E-12 FOXO3, AKT1, AKT3, regulating PIK3CB, PIK3CA, pathway - PIK3R1, IRS1, PIK3R2 multiple HRAS species hsa04919 Thyroid 56.536939 10 6.5E-12 6.5E-12 PIK3CB, AKT1, AKT3, hormone PIK3R1, PDPK1, signaling PLCG2, PIK3CA, pathway HRAS, PIK3R2, MAP2K2, GSK3B, TP53 PLCG1, MAPK3 hsa04630 Jak-STAT 34.600473 10 7.4E-12 5.7E-11 PIK3CB, AKT1, AKT3, signaling PIK3R1, PIK3CA, pathway HRAS PIK3R2, SOS1, SOS2, GRB2, PTPN11 hsa04152 AMPK 55.518255 10 8.2E-12 8.2E-12 PIK3CB, AKT1, AKT3, signaling PIK3R1, IRS1, PIK3CA, pathway FOXO3 PIK3R2, PDPK1 hsa04066 HIF-1 47.136876 10 8.4E-12 5.3E-11 PIK3CB, PIK3CA, signaling PIK3R1, PIK3R2, AKT1, pathway PLCG2, AKT3, PLCG1, CAMK2A, NFKB1, RELA, CAMK2D, MAPK3 CAMK2G, MAP2K2 ID Pathway Fold_Enric occurre lowest_p highest_ Positively_corr Negatively_corr hment nce p elated elated hsa04015 Rap1 30.115226 10 8.9E-12 2E-09 MAP2K2, MAPK3, signaling CRK, RHOA, RAP1B, NGF, pathway PIK3CB, NGFR, RAC1, PIK3R1, MAPK11, HRAS BRAF, RAPGEF1, CDC42, PIK3CA, PIK3R2, AKT1, AKT3, CALM3, PLCG1 hsa05162 Measles 61.951323 10 1.2E-11 4.9E-10 IRAK4, NFKB1, RELA, NFKBIA, PIK3CA, NFKBIB, PIK3R2, AKT1, PIK3CB, AKT3, TP73, PIK3R1, TP53 GSK3B hsa04211 Longevity 65.758665 10 1.3E-11 7E-11 FOXO3, AKT1, AKT3, regulating PIK3CB, PIK3CA, pathway PIK3R1, IRS1, PIK3R2, HRAS, ATF4, NFKB1, RELA TP53, BAX, CAMK4 hsa04137 Mitophagy - 73.023521 10 1.9E-11 9.5E-11 ATF4, TP53, RELA, MAPK8, animal HRAS, JUN, MAPK9, FOXO3 MAPK10 hsa05230 Central 63.241975 10 2.9E-11 1.4E-10 HRAS, NTRK3, carbon MAP2K2, MAPK3, metabolism in PIK3CB, PIK3CA, cancer PIK3R1, TP53 PIK3R2, AKT1, AKT3 hsa05222 Small cell 77.615152 10 2.9E-11 6.5E-11 PIK3CB, AKT1, AKT3, lung cancer PIK3R1, PIK3CA, IKBKB, PIK3R2, NFKBIA, BAX, NFKB1, RELA TP53 hsa05219 Bladder 178.4878 10 4.4E-11 4.8E-07 HRAS, TP53, RPS6KA5, cancer MAP2K2 MAPK3, BRAF hsa05165 Human 19.222485 10 6.9E-11 7.4E-10 PIK3CB, AKT1, AKT3, papillomaviru PIK3R1, TP53, PIK3CA, s infection IKBKB, HRAS, PIK3R2, MAP2K2, BAX GSK3B, NFKB1, RELA, GRB2, SOS1, SOS2, MAPK3, CDC42 hsa04750 Inflammatory 69.130904 10 1.2E-10 1.2E-10 CAMK2A, NGF, MAPK8, mediator CAMK2D, MAPK11, regulation of CAMK2G, MAPK9, TRP PLCG2, MAPK10, channels PIK3CB, PLCG1, PIK3R1 PIK3CA, PIK3R2, CALM3 hsa04923 Regulation of 100.47597 10 2.8E-10 2.8E-10 PIK3CB, PIK3CA, lipolysis in PIK3R1, IRS1 PIK3R2, AKT1, adipocytes AKT3 ID Pathway Fold_Enric occurre lowest_p highest_ Positively_corr Negatively_corr hment nce p elated elated hsa04810 Regulation of 26.229391 10 3E-10 6.5E-08 RHOA, CDC42, RAC1, actin MAP2K2, MAPK3, BRAF, cytoskeleton PIK3CB, PIK3CA, PIK3R1, CRK, PIK3R2, SOS1, HRAS SOS2 hsa05216 Thyroid 203.27778 10 4.4E-10 1.3E-05 HRAS, BRAF, MAPK3 cancer MAP2K2, TP53, BAX hsa04623 Cytosolic 108.41481 10 4.8E-10 3.1E-08 IKBKB, NFKB1, RELA DNA-sensing NFKBIA, pathway NFKBIB hsa04218 Cellular 44.935088 10 5.6E-10 3.7E-09 TP53, PIK3CA, senescence PIK3CB, PIK3R2, AKT1, PIK3R1, AKT3, MAPK3, FOXO3, MAPK11, HRAS, NFKB1, RELA, MAP2K2, CALM3 MAPKAPK2 hsa05140 Leishmaniasi 84.846377 10 6.5E-10 4.4E-08 NFKBIA, NFKB1, RELA, s NFKBIB, MAPK3, IRAK4, JUN MAPK11 hsa04666 Fc gamma R- 45.17284 10 9.5E-10 6E-09 PIK3CB, PIK3CA, mediated PIK3R1, PIK3R2, phagocytosis PLCG2, CRK PLCG1, MAPK3, AKT1, AKT3, RAC1, CDC42 hsa04310 Wnt signaling 59.016129 10 1.1E-09 1.1E-08 CAMK2A, MAPK8, pathway CAMK2D, MAPK9, CAMK2G, MAPK10, RHOA, JUN, RAC1, GSK3B TP53 hsa04530 Tight junction 49.445946 10 1.8E-09 4.3E-08 RHOA, CDC42, RAC1, MAP2K7, MAPK8, MAP3K1, JUN MAPK9, MAPK10 hsa04730 Long-term 138.07547 10 2.6E-09 2E-05 MAP2K2, MAPK3, BRAF depression HRAS hsa04720 Long-term 63.634783 10 3.8E-09 1.3E-08 CAMK4, CALM3, potentiation CAMK2A, MAPK3, BRAF, CAMK2D, RAP1B CAMK2G, RPS6KA1, ATF4, MAP2K2, HRAS hsa04960 Aldosterone- 113.28173 10 4.3E-09 4.3E-09 IRS1, PIK3CB, PIK3CA, regulated PIK3R1 PIK3R2, sodium PDPK1, reabsorption MAPK3 hsa04215 Apoptosis - 99.429348 10 7.9E-09 1.1E-05 BAX MAPK8, multiple MAPK9, species MAPK10, NGFR ID Pathway Fold_Enric occurre lowest_p highest_ Positively_corr Negatively_corr hment nce p elated elated hsa04973 Carbohydrate 132.81307 10 1E-08 1E-08 PIK3CB, PIK3CA, digestion and PIK3R1 PIK3R2, AKT1, absorption AKT3 hsa04540 Gap junction 35.199615 10 1.3E-08 2.1E-06 MAP2K5, MAPK7, MAP2K2, MAPK3, SOS1, HRAS SOS2, GRB2 hsa05152 Tuberculosis 36.59 10 1.9E-08 1.9E-06 CAMK2A, CALM3, CAMK2D, MAPK3, CAMK2G, NFKB1, RELA, IRAK4, BAX, AKT1, AKT3, RHOA, RIPK2 MAPK8, MAPK9, MAPK10, MAPK11, IRAK2 hsa04725 Cholinergic 48.144737 10 2E-08 2E-08 ATF4, MAPK3, synapse CAMK4, PIK3CA, CAMK2A, PIK3R2, AKT1, CAMK2D, AKT3 CAMK2G, PIK3CB, PIK3R1, HRAS hsa04360 Axon 26.535095 10 2.2E-08 1E-07 RHOA, HRAS, MAPK3, RAC1, guidance CAMK2A, CDC42, ABL1, CAMK2D, PIK3CA, CAMK2G, PIK3R2, PIK3CB, GSK3B, PIK3R1, PLCG1, PLCG2 PTPN11 hsa04921 Oxytocin 36.813511 10 3.4E-08 7.1E-06 HRAS, CALM3, signaling MAP2K2, MAPK3, pathway CAMK4, MAPK7 CAMK2A, CAMK2D, CAMK2G, RHOA, MAP2K5, JUN hsa04728 Dopaminergic 38.197477 10 5.1E-08 5.1E-08 ATF4, AKT1, AKT3, synapse CAMK2A, GSK3B, CAMK2D, MAPK8, CAMK2G MAPK11, MAPK9, MAPK10, CALM3 hsa04670 Leukocyte 33.188209 10 5.2E-08 1.9E-07 PIK3CB, PTPN11, transendothel PIK3R1, PIK3CA, ial migration RHOA, PIK3R2, PLCG2 MAPK11, RAC1, RAP1B, PLCG1, CDC42 ID Pathway Fold_Enric occurre lowest_p highest_ Positively_corr Negatively_corr hment nce p elated elated hsa04550 Signaling 38.515789 10 7.3E-08 7.3E-08 PIK3CB, GSK3B, pathways PIK3R1, PIK3CA, regulating HRAS, PIK3R2, AKT1, pluripotency MAP2K2 AKT3, GRB2, of stem cells MAPK3, MAPK11 hsa05034 Alcoholism 27.900871 10 9.3E-08 2.4E-06 ATF4, CALM3, BRAF, CAMK4, MAPK3, SHC4, HRAS, SHC1, GRB2, SOS1, SHC2 SOS2 hsa04371 Apelin 45.7375 10 1E-07 0.00119 MAP2K2, AKT1, AKT3, signaling HRAS, MAPK3, pathway CAMK4 CALM3 hsa05321 Inflammatory 102.70877 10 2.1E-07 7.8E-05 JUN NFKB1, RELA bowel disease (IBD) hsa04064 NF-kappa B 54.207407 10 2.4E-07 1.3E-05 NFKBIA, NFKB1, RELA, signaling IRAK4, IKBKB, PLCG1 pathway PLCG2 hsa05030 Cocaine 95.452174 10 5E-07 2E-05 JUN, ATF4 NFKB1, RELA addiction hsa05031 Amphetamine 52.159658 10 5.2E-07 4.7E-05 CAMK4, CALM3 addiction CAMK2A, CAMK2D, CAMK2G, ATF4, JUN hsa04070 Phosphatidyli 46.970475 10 5.5E-07 5.5E-07 PLCG2, PLCG1, nositol PIK3CB, CALM3, signaling PIK3R1 PIK3CA, system PIK3R2 hsa04261 Adrenergic 31.817391 10 5.7E-07 0.00023 ATF4, AKT1, AKT3, signaling in CAMK2A, MAPK3, cardiomyocyt CAMK2D, CALM3, es CAMK2G MAPK11, RPS6KA5 hsa05146 Amoebiasis 68.875294 10 8.1E-07 6.1E-06 PIK3CB, NFKB1, RELA, PIK3R1 PIK3CA, PIK3R2 hsa04723 Retrograde 33.645977 10 1.1E-06 0.00055 MAPK3, endocannabi MAPK8, noid signaling MAPK11, MAPK9, MAPK10 hsa04922 Glucagon 36.156126 10 1.3E-06 0.00013 ATF4, AKT1, AKT3, signaling CAMK2A, CALM3 pathway CAMK2D, CAMK2G hsa04611 Platelet 35.996065 10 1.6E-06 1.6E-06 PLCG2, RAP1B, activation PIK3CB, PIK3CA, PIK3R1, PIK3R2, AKT1, RHOA AKT3, MAPK11, MAPK3 ID Pathway Fold_Enric occurre lowest_p highest_ Positively_corr Negatively_corr hment nce p elated elated hsa04916 Melanogenesi 31.424584 10 1.7E-06 7.9E-05 CAMK2A, CALM3, s CAMK2D, GSK3B, CAMK2G, MAPK3 MAP2K2, HRAS hsa04934 Cushing's 25.659187 10 1.8E-06 1.9E-05 ATF4, GSK3B, syndrome CAMK2A, MAPK3, CAMK2D, RAP1B, BRAF CAMK2G, MAP2K2 hsa04726 Serotonergic 57.171875 10 2.4E-06 0.00619 HRAS MAPK3, BRAF synapse hsa04270 Vascular 61.668539 10 3.2E-06 0.00017 RHOA, CALM3, BRAF, smooth MAP2K2 MAPK3 muscle contraction hsa05020 Prion 114.34375 10 5.5E-06 0.00116 BAX, MAP2K2 MAPK3 diseases hsa00562 Inositol 50.512511 10 7.5E-06 7.5E-06 PLCG2, PLCG1, phosphate PIK3CB PIK3CA metabolism hsa04141 Protein 17.676329 10 1.4E-05 0.00199 ATF4, MAPK8, processing in MAP2K7, BAX MAPK9, endoplasmic MAPK10 reticulum hsa04022 cGMP-PKG 33.013534 10 1.4E-05 0.00078 RHOA, MAPK3, AKT1, signaling MAP2K2, AKT3, CALM3 pathway ATF4, IRS1 hsa05202 Transcription 15.426614 10 1.5E-05 0.00061 TP53, BAX NGFR, NFKB1, al RELA misregulation in cancer hsa05014 Amyotrophic 58.544 10 1.7E-05 0.00011 BAX, TP53 MAPK11, lateral RAC1 sclerosis (ALS) hsa05134 Legionellosis 73.919192 10 1.9E-05 6.3E-05 NFKBIA NFKB1, RELA hsa04520 Adherens 60.479339 10 2.8E-05 0.00668 RHOA MAPK3, RAC1, junction CDC42 hsa04110 Cell cycle 20.863863 10 3.4E-05 0.00047 YWHAE, TP53 GSK3B, ABL1 hsa04114 Oocyte 25.711023 10 4.1E-05 0.00021 RPS6KA1, MAPK3, meiosis CAMK2A, CALM3 CAMK2D, CAMK2G, YWHAE hsa04713 Circadian 31.817391 10 6.7E-05 0.00416 CAMK2A, CALM3, entrainment CAMK2D, MAPK3, CAMK2G RPS6KA5 hsa04925 Aldosterone 33.491991 10 6.7E-05 0.00416 ATF4, CALM3 synthesis and CAMK4, secretion CAMK2A, CAMK2D, CAMK2G ID Pathway Fold_Enric occurre lowest_p highest_ Positively_corr Negatively_corr hment nce p elated elated hsa04390 Hippo 18.069136 10 8E-05 0.00464 YWHAE TP73, GSK3B signaling pathway hsa04928 Parathyroid 40.655556 10 0.00014 0.00594 RHOA, ATF4 BRAF, MAPK3 hormone synthesis, secretion and action hsa04217 Necroptosis 18.052421 10 0.00015 0.0011 BAX, MAPK8, CAMK2A, MAPK9, CAMK2D, MAPK10 CAMK2G hsa05130 Pathogenic 58.079365 10 0.00016 0.0002 RHOA CDC42, ABL1 Escherichia coli infection hsa04115 p53 signaling 29.3699 10 0.00019 0.00053 BAX, TP53 TP73 pathway hsa04714 Thermogenes 14.671211 10 0.00023 0.00315 RPS6KA1, MAPK11, is HRAS FRS2, GRB2, SOS1, SOS2 hsa05217 Basal cell 37.432225 10 0.00037 0.0041 TP53, BAX GSK3B carcinoma hsa04971 Gastric acid 35.352657 10 0.0005 0.00668 CAMK2A, CALM3 secretion CAMK2D, CAMK2G hsa04020 Calcium 17.676329 10 0.00067 0.00531 CAMK4, PLCG1, signaling CAMK2A, CALM3 pathway CAMK2D, CAMK2G, PLCG2 hsa04911 Insulin 28.493186 10 0.00071 0.01042 ATF4, secretion CAMK2A, CAMK2D, CAMK2G hsa04144 Endocytosis 14.191338 10 0.00076 0.00624 HRAS, RHOA CDC42 hsa05010 Alzheimer's 19.274802 10 0.00118 0.00437 PSEN2 MAPK3, disease CALM3, GSK3B hsa05110 Vibrio 25.813051 10 0.00201 0.01166 PLCG2 PLCG1 cholerae infection hsa04340 Hedgehog 56.292308 2 0.00222 0.00231 GSK3B signaling pathway hsa04962 Vasopressin- 91.475 10 0.0025 0.00487 ARHGDIG ARHGDIA regulated water reabsorption hsa04350 TGF-beta 57.283757 6 0.00334 0.02161 RHOA MAPK3 signaling pathway hsa04972 Pancreatic 36.4533 10 0.00339 0.01249 RHOA RAP1B, RAC1 secretion hsa05416 Viral 78.90027 5 0.00341 0.00914 ABL1, RAC1 myocarditis ID Pathway Fold_Enric occurre lowest_p highest_ Positively_corr Negatively_corr hment nce p elated elated hsa05323 Rheumatoid 50.996516 2 0.00481 0.00481 JUN arthritis hsa04120 Ubiquitin 18.340852 10 0.00705 0.02514 MAP3K1 mediated proteolysis hsa05016 Huntington's 17.623119 10 0.0094 0.03118 TP53, BAX disease hsa04330 Notch 221.75758 2 0.01006 0.01006 PSEN2 signaling pathway hsa04724 Glutamatergi 23.492777 1 0.01549 0.01549 MAPK3 c synapse hsa04740 Olfactory 64.192982 1 0.04474 0.04474 CAMK2A, CALM3 transduction CAMK2D, CAMK2G hsa05310 Asthma 159.08696 1 0.0499 0.0499 Supplementary Table S2: Enrichment analysis (KEGG pathways) of BMI1 correlated genes.

ID Pathway Fold_ occurr lowest_ highest_ Positively_correlat Negatively_correlat Enrich ence p p ed ed ment hsa04010 MAPK 53.03 10 7E-78 1.27E-65 RASGRF1, RASGRF2, signaling DUSP4, DUSP5, DUSP1, DUSP2, pathway DUSP3, PTPRR, DUSP6, DUSP7, PTPN5, PPM1B, DUSP8, DUSP9, MAP4K4, DUSP10, DUSP16, STMN1, MAPT, PTPN7, PLA2G4A, CHUK, IKBKG, NFKB1, NFKB2, MAPK1, RAF1, RELA, RELB, BRAF, RASA1, IKBKB, MAP2K2, NF1, RAP1A, PRKCA, PRKCG, PRKACA, HRAS, RRAS, PRKACB, RASGRP3, RAPGEF2, RASGRP4, EGFR, RASA2, RRAS2, FGFR3, FGFR2, MRAS, FGFR4, NTRK1, RASGRP2, PDGFRA, SOS1, SOS2, PDGFRB, GNA12, GRB2, CACNA1B, NTRK2, CACNA1S, CACNA1A, CACNB2, CACNA1C, CACNA1I, CACNA1E, CACNG5, CACNA1F, CACNG4, NR4A1, CACNA2D1, CDC25B, CACNB1, RPS6KA4, CACNB3, MAPKAPK3, CACNG1, MAPKAPK2, CACNA1H, ATF4, MEF2C, CACNA2D2, DDIT3, TP53, CACNG3, ELK1, MAP2K6, CACNG2, NLK, MAP2K3, AKT2, RPS6KA5, ELK4, MAP3K4, HSPB1, ATF2, MAPK14, MAP3K6, MAPK11, MAP3K12, STK3, MAPK13, ECSIT, GADD45A, PPM1A, AKT3, GADD45B, DAXX, TAOK2, TAOK3, CD14, FAS, IL1R1, TAOK1, MAP3K7, TNFRSF1A, MAP3K13, TGFB2, IL1B, MAP4K2, STK4, RAC2, MAPK8IP2, TAB2, TAB1, MAP3K11, GADD45G, MAP2K7, TRAF6, CASP3, MAPK10, ARRB2, TGFB3, CDC42, HSPA2, HSPA6, RAC1, PAK1, JUND, JUN, PAK2, MAP3K2, NFATC3, MAPK8IP1, NFATC1, FLNA, MAPK8, MAPK9, FLNB, FLNC, ARRB1, HSPA1L, MAP3K1, HSPA8, PPP3CA, MAP3K8, PPP3CB, MAP4K1, FOS, PPP3R1, SRF, MYC, PPP3R2, RPS6KA1, MAP4K3, RPS6KA2, MKNK1, FGF9, RPS6KA3, NTF3, FGF16 MKNK2, BDNF, FGF1, FGF3, FGF5, FGF7, FGF8, FGF10, PDGFB, FGF18, FGF17, FGF19, FGF20 ID Pathway Fold_ occurr lowest_ highest_ Positively_correlat Negatively_correlat Enrich ence p p ed ed ment hsa05161 Hepatitis 67.88 10 1E-24 7.18E-23 CASP3, RAF1, PRKCA, PRKCG, B MAPK1, ATF2, MAP2K2, FOS, GRB2, MAPK8, NFKB1, RELA, MAPK9, AKT3, MYC, ELK1, ATF4, CHUK, IKBKG, HRAS, MAP3K1, TGFB3 MAPK10, JUN, NFATC1, NFATC3, TP53, AKT2, IKBKB, FAS, TGFB2 hsa05169 Epstein- 34.65 10 4E-24 7.6E-22 CHUK, TRAF6, MYC, TP53, Barr TAB1, TAB2, NFKB1, RELA, virus MAP3K7, NFKB2, RELB, infection MAPK8, MAPK9, MAP2K7, MAPK14, MAP2K3, MAPK11, MAP2K6, MAPK13, AKT3, MAPK10, JUN, GADD45G, AKT2, GADD45A, RAC1, IKBKG, GADD45B, IKBKB, CASP3 FAS hsa04912 GnRH 79.3 10 4E-22 3.41E-20 CDC42, MAPK14, PRKCA, ATF4, signaling MAPK11, MAP2K3, pathway MAPK13, MAP2K6, MAP3K2, MAP3K1, PRKACA, MAP3K4, PRKACB, PLA2G4A, CACNA1C, CACNA1S, ELK1, CACNA1F, MAP2K2, HRAS, MAPK1, RAF1, EGFR, MAP2K7, SOS1, SOS2, MAPK10, JUN GRB2, MAPK8, MAPK9 hsa05205 Proteogl 45.8 10 7E-21 4.28E-13 AKT3, RAC1, AKT2, FLNA, ycans in CDC42, PAK1, FLNB, FLNC, cancer MAPK1, RRAS2, ELK1, HRAS, MRAS, BRAF, RRAS, MAP2K2, RAF1, GRB2, TP53, PRKCA, SOS1, SOS2, MYC, FAS, PRKACA, TGFB2, PRKCG, PRKACB, EGFR MAPK14, MAPK11, MAPK13, CASP3 hsa04668 TNF 73.18 10 1E-20 5.54E-17 MAP3K7, TNFRSF1A, signaling MAPK14, MAP2K7, pathway MAPK11, MAP2K3, MAPK13, MAP2K6, MAPK8, MAPK9, MAPK10, IKBKB, IKBKG, MAPK1, NFKB1, RELA, RPS6KA5, ATF2, MAP3K8, CASP3, AKT3, RPS6KA4, ATF4, CHUK, TAB1, JUN, FAS, IL1B, TAB2 FOS, AKT2 ID Pathway Fold_ occurr lowest_ highest_ Positively_correlat Negatively_correlat Enrich ence p p ed ed ment hsa04014 Ras 39.42 10 4E-20 1.8E-19 MAPK1, RAF1, MAP2K2, HRAS, signaling RRAS2, MRAS, RRAS, AKT2, pathway GRB2, SOS1, BDNF, FGF1, SOS2, AKT3, FGF3, FGF5, FGF9, NTF3, FGF7, FGF8, FGF16, NTRK2, FGF10, PDGFB, RAC1, CHUK, FGF18, FGF17, IKBKG, MAPK8, FGF19, FGF20, MAPK9, CDC42, EGFR, FGFR3, RASGRP2, FGFR2, FGFR4, RASGRF1, NTRK1, PDGFRA, RASA1, RASA2, PDGFRB, RAC2, NF1, STK4, PRKCA, PRKCG, RAP1A, PAK1, IKBKB, NFKB1, PAK2, PRKACA, RELA, MAPK10, PRKACB PLA2G4A, ELK1, RASGRP3, RASGRP4, RASGRF2 hsa04722 Neurotro 49.38 10 6E-20 2.17E-17 NTRK2, NTF3, NTRK1, BDNF, phin GRB2, AKT3, AKT2, HRAS, signaling BRAF, RAF1, MAP2K2, pathway SOS1, SOS2, RPS6KA1, MAPK1, RAP1A, RPS6KA2, RPS6KA5, RPS6KA3, NFKB1, MAPK8, MAPK9, RELA, ATF4, MAPK14, MAPK10, TP53, MAPK11, MAP3K1, JUN, MAPK13, CDC42, MAPKAPK2, RAC1, TRAF6 MAP2K7, IKBKB hsa04380 Osteocl 65.05 10 7E-20 1E-17 TRAF6, CHUK, IKBKB, NFKB1, ast IKBKG, MAP3K7, RELA, MAP2K6, differenti TAB1, TAB2, MAPK10, ation MAPK8, MAPK9, NFATC1, AKT2, MAPK14, IL1B, IL1R1, FOS, MAPK11, JUN, JUND, MAPK13, AKT3, TNFRSF1A, PPP3CA, TGFB2, NFKB2, PPP3CB, RELB, MAP2K7 PPP3R1, PPP3R2, GRB2, MAPK1, RAC1 hsa04625 C-type 62.95 10 3E-19 4.28E-17 RAF1, PAK1, NFKB1, HRAS, lectin RRAS2, MRAS, RRAS, RELA, receptor IKBKG, CHUK, IKBKB, IL1B, signaling MAPK1, MAPKAPK2, pathway PPP3CA, NFATC1, PPP3CB, NFATC3, AKT2, PPP3R1, NFKB2, RELB, PPP3R2, AKT3, MAPK10, JUN MAPK14, MAPK11, MAPK13, MAPK8, MAPK9 ID Pathway Fold_ occurr lowest_ highest_ Positively_correlat Negatively_correlat Enrich ence p p ed ed ment hsa04620 Toll-like 76.36 10 7E-19 5.71E-17 CHUK, TRAF6, MAP3K8, NFKB1, receptor MAPK1, IKBKB, MAPK10, signaling MAP3K7, IL1B, AKT2, CD14, pathway MAPK14, MAP2K7, RELA, MAPK11, MAP2K3, MAPK13, RAC1, MAP2K6, MAPK8, MAPK9, MAP2K2, FOS, TAB1, AKT3, JUN TAB2, IKBKG hsa05145 Toxopla 59.83 10 1E-18 1.94E-18 TRAF6, MAP3K7, IKBKB, NFKB1, smosis TAB1, TAB2, RELA, MAPK10, CHUK, IKBKG, MAP2K3, MAPK1, MAPK8, MAP2K6, AKT2, MAPK9, HSPA2, HSPA6, MAPK14, TNFRSF1A, MAPK11, TGFB2 MAPK13, CASP3, AKT3, HSPA1L, HSPA8, TGFB3 hsa05160 Hepatitis 49.61 10 2E-18 3.81E-16 CHUK, IKBKG, NFKB1, RELA, C TRAF6, MAPK1, IKBKB, EGFR, GRB2, SOS1, HRAS, AKT2, SOS2, BRAF, TP53, TNFRSF1A, RAF1, AKT3, MAP2K2, FAS, CASP3 MYC hsa05200 Pathway 14.83 10 2E-18 1.4E-15 CASP3, CHUK, EGFR, PDGFRA, s in IKBKG, GRB2, PDGFRB, FGFR3, cancer SOS1, SOS2, FGFR2, FGFR4, BRAF, RAF1, NTRK1, PDGFB, STK4, RAC1, IKBKB, HRAS, MAPK8, MAPK9, MAP2K2, NFKB1, CDC42, TGFB3, NFKB2, RELA, TRAF6, MAPK1, RAC2, MAPK10, AKT3, FGF9, JUN, FOS, MYC, FGF16, PRKACA, TP53, PRKCA, PRKACB, PRKCG, TGFB2, GNA12, FAS, AKT2, FGF1, RASGRP2, FGF3, FGF5, GADD45G, FGF7, FGF8, RPS6KA5 FGF10, FGF18, FGF17, FGF19, FGF20, RASGRP3, RASGRP4, GADD45A, GADD45B, ELK1 hsa05167 Kaposi's 39.48 10 7E-18 1.7E-17 CHUK, IKBKG, IKBKB, MAPK10, sarcoma MAPK8, MAPK9, AKT2, NFKB1, - AKT3, CASP3, RELA, FAS, associat PPP3CA, TNFRSF1A, TP53, ed PPP3CB, PDGFB, NFATC1, herpesvi PPP3R1, NFATC3, HRAS, rus PPP3R2, RAF1, MAP2K2, FOS, infection MAPK1, RAC1, JUN, MYC, MAPK14, MAPKAPK2, MAPK11, MAP2K6, MAP2K7 MAPK13 ID Pathway Fold_ occurr lowest_ highest_ Positively_correlat Negatively_correlat Enrich ence p p ed ed ment hsa04660 T cell 67.79 10 1E-17 1.16E-15 IKBKG, CHUK, NFKB1, RELA, receptor AKT3, GRB2, IKBKB, MAP3K8, signaling SOS1, SOS2, AKT2, HRAS, pathway PPP3CA, FOS, JUN, PPP3CB, NFATC1, PPP3R1, NFATC3, PPP3R2, CDC42, MAP2K2, MAP2K7 PAK1, PAK2, RAF1, MAPK1, MAP3K7, MAPK9, MAPK14, MAPK11, MAPK13 hsa05212 Pancrea 71.55 10 2E-17 3E-15 AKT3, RAC1, AKT2, RAC2, tic CHUK, IKBKG, IKBKB, NFKB1, cancer BRAF, RAF1, RELA, MAPK10, MAPK1, MAPK8, TGFB2, EGFR, MAPK9, CDC42, TP53, GADD45A, TGFB3, GADD45B GADD45G hsa04926 Relaxin 39.05 10 2E-17 1.9E-15 AKT3, MAPK1, AKT2, NFKB1, signaling ATF2, PRKACA, RELA, ATF4, pathway PRKACB, RAF1, HRAS, MAP2K2, SOS1, SOS2, PRKCA, FOS, MAPK14, JUN, MAP2K7, MAPK11, MAPK10, EGFR, MAPK13, ARRB2 MAPK8, MAPK9, GRB2, ARRB1 hsa04657 IL-17 92.63 10 2E-17 2.78E-15 MAP3K7, CHUK, IKBKB, NFKB1, signaling TRAF6, TAB2, RELA, FOS, JUN, pathway IKBKG, MAPK14, JUND, MAPK10, MAPK1, MAPK8, IL1B MAPK11, MAPK9, MAPK13, CASP3 hsa05418 Fluid 53.63 10 2E-17 8.68E-16 MAPK14, FOS, JUN, AKT2, shear MAPK11, MAPK10, MEF2C, stress MAPK13, AKT3, MAP2K7, and MAPK8, MAPK9, MAP2K6, RAC2, atherosc RAC1, MAP3K7, IL1B, PDGFB, lerosis CHUK, IKBKG TP53, TNFRSF1A, IL1R1, IKBKB, NFKB1, RELA, DUSP1 hsa05231 Choline 52.93 10 3E-17 3.16E-15 MAPK8, MAPK9, MAPK10, HRAS, metaboli MAPK1, SOS1, MAP2K2, AKT2, sm in SOS2, RAF1, EGFR, PDGFRA, cancer AKT3, GRB2, PDGFRB, PDGFB, RAC1 PLA2G4A, RAC2, FOS, JUN, PRKCA, PRKCG ID Pathway Fold_ occurr lowest_ highest_ Positively_correlat Negatively_correlat Enrich ence p p ed ed ment hsa05214 Glioma 56.37 10 3E-17 3.61E-15 GRB2, SOS1, PDGFB, EGFR, SOS2, BRAF, PDGFRA, RAF1, MAPK1, PDGFRB, PRKCA, AKT3, GADD45G PRKCG, MAP2K2, AKT2, TP53, HRAS, GADD45A, GADD45B hsa04068 FoxO 46.1 10 9E-17 1.33E-14 CHUK, MAPK8, IKBKB, MAPK10, signaling MAPK9, MAPK1, HRAS, MAP2K2, pathway SOS1, SOS2, AKT2, EGFR, BRAF, RAF1, GADD45A, AKT3, GRB2, GADD45B, TGFB2 STK4, GADD45G, NLK, MAPK14, MAPK11, MAPK13, TGFB3 hsa04915 Estroge 42.34 10 1E-16 5.54E-15 PRKACA, EGFR, FOS, JUN, n PRKACB, RAF1, HRAS, MAP2K2, signaling MAPK1, ATF2, ATF4, AKT2, pathway AKT3, GRB2, HSPA2, HSPA6 SOS1, SOS2, HSPA1L, HSPA8 hsa04012 ErbB 47.32 10 2E-16 2.19E-14 GRB2, PAK1, ELK1, EGFR, signaling PAK2, MAPK8, MAP2K7, pathway MAPK9, SOS1, MAPK10, PRKCA, SOS2, AKT3, PRKCG, JUN, MAPK1, BRAF, AKT2, MYC, RAF1 MAP2K2, HRAS hsa05210 Colorect 45.1 10 2E-16 2.6E-14 CASP3, TGFB3, TGFB2, MAPK10, al BRAF, RAF1, RAC2, MYC, cancer MAPK8, MAPK9, MAP2K2, JUN, RAC1, MAPK1, FOS, TP53, AKT2, AKT3, GADD45A, GADD45G, GADD45B, HRAS, SOS1, SOS2, EGFR GRB2 hsa05168 Herpes 46.15 10 3E-16 9E-13 MAPK8, MAPK9, MAPK10, NFKB1, simplex TAB1, TAB2, RELA, FOS, JUN, infection MAP3K7, IKBKG, IL1B, DAXX, TP53, TRAF6, CASP3, FAS, TNFRSF1A, CHUK IKBKB hsa04658 Th1 and 63.14 10 4E-16 4.69E-16 CHUK, IKBKG, NFKB1, RELA, Th2 cell PPP3CA, IKBKB, NFATC1, differenti PPP3CB, NFATC3, ation PPP3R1, MAPK10, JUN, PPP3R2, MAPK1, FOS MAPK14, MAPK11, MAPK13, MAPK8, MAPK9 ID Pathway Fold_ occurr lowest_ highest_ Positively_correlat Negatively_correlat Enrich ence p p ed ed ment hsa05166 HTLV-I 32.39 10 5E-16 4.35E-14 PPP3CA, NFATC1, infection PPP3CB, NFATC3, MYC, PPP3R1, HRAS, ATF4, PPP3R2, TGFB2, NFKB1, PRKACA, RELA, NFKB2, PRKACB, ATF2, RELB, IKBKB, TGFB3, CHUK, TNFRSF1A, IKBKG, MAPK8, IL1R1, MAP3K1, MAPK9, AKT3, MAPK10, JUN, ELK4, MAPK1 AKT2, SRF, ELK1, FOS, MAP2K2, TP53 hsa05215 Prostate 43.39 10 8E-16 4.7E-14 CHUK, IKBKG, NFKB1, RELA, cancer SOS1, SOS2, HRAS, TP53, GRB2, AKT3, EGFR, FGFR2, MAPK1, BRAF, PDGFRA, RAF1 PDGFRB, IKBKB, ATF4, PDGFB, AKT2, MAP2K2 hsa04664 Fc 55.31 10 8E-16 1.06E-13 AKT3, MAPK14, AKT2, MAP2K7, epsilon MAPK11, MAP2K3, RI MAPK13, MAP2K6, PRKCA, signaling MAPK1, RAF1, MAP2K2, HRAS, pathway SOS1, SOS2, PLA2G4A, GRB2, MAPK8, MAPK10, RAC2 MAPK9, RAC1 hsa04659 Th17 53.67 10 2E-15 2.09E-15 CHUK, IKBKG, NFKB1, RELA, cell PPP3CA, IKBKB, NFATC1, differenti PPP3CB, NFATC3, ation PPP3R1, MAPK10, JUN, PPP3R2, MAPK1, FOS, IL1R1, IL1B MAPK14, MAPK11, MAPK13, MAPK8, MAPK9 hsa04064 NF- 73.92 10 2E-15 1.53E-13 CHUK, IKBKG, IL1R1, kappa B MAP3K7, TRAF6, TNFRSF1A, IL1B, signaling TAB1, TAB2 IKBKB, NFKB2, pathway RELB, NFKB1, RELA, CD14, GADD45B hsa04151 PI3K- 18.07 10 3E-15 2.78E-13 AKT3, NTRK2, AKT2, EGFR, Akt CHUK, IKBKG, FGFR3, FGFR2, signaling FGF9, NTF3, FGFR4, NTRK1, pathway FGF16, GRB2, PDGFRA, SOS1, SOS2, PDGFRB, MYC, RAF1, MAPK1, TP53, IKBKB, RAC1, ATF2 NFKB1, RELA, BDNF, FGF1, FGF3, FGF5, FGF7, FGF8, FGF10, PDGFB, FGF18, FGF17, FGF19, FGF20, HRAS, MAP2K2, ATF4, PRKCA, NR4A1 ID Pathway Fold_ occurr lowest_ highest_ Positively_correlat Negatively_correlat Enrich ence p p ed ed ment hsa05120 Epithelia 81.06 10 5E-15 1.45E-13 MAPK14, JUN, MAPK10, l cell MAPK11, IKBKB, NFKB1, signaling MAPK13, RELA, EGFR in MAPK8, MAPK9, Helicoba CHUK, IKBKG, cter CASP3, PAK1, pylori CDC42, RAC1 infection hsa05224 Breast 48.14 10 5E-15 7.51E-11 BRAF, RAF1, EGFR, HRAS, cancer MAPK1, GRB2, MAP2K2, FOS, SOS1, SOS2, JUN, AKT2, MYC, AKT3, FGF9, NFKB2, FGF1, FGF16, FGF3, FGF5, GADD45G FGF7, FGF8, FGF10, FGF18, FGF17, FGF19, FGF20, TP53, GADD45A, GADD45B hsa04621 NOD- 49.45 10 6E-15 2.32E-11 CHUK, MAP3K7, IKBKB, IL1B, like TAB1, TAB2, MAPK10, NFKB1, receptor MAPK8, MAPK9, RELA, JUN signaling MAPK1, pathway MAPK14, MAPK11, MAPK13, IKBKG, TRAF6 hsa05219 Bladder 150.3 10 6E-15 1.36E-14 RPS6KA5, HRAS, EGFR, cancer MAPK1, BRAF, MYC, TP53, RAF1 FGFR3, MAP2K2 hsa04810 Regulati 45.56 10 7E-15 4.28E-13 PAK1, PAK2, RAC2, MAP2K2, on of CDC42, RAC1, HRAS, RRAS, actin MAPK1, BRAF, EGFR, FGFR3, cytoskel MOS, RAF1, FGFR2, FGFR4, eton RRAS2, MRAS, PDGFRA, GNA12, SOS1, PDGFRB, FGF1, SOS2, FGF9, FGF3, FGF5, FGF16 FGF7, FGF8, FGF10, PDGFB, FGF18, FGF17, FGF19, FGF20 hsa05218 Melano 93.37 10 8E-15 6.63E-13 BRAF, FGF9, EGFR, PDGFRA, ma FGF16, AKT3, PDGFRB, FGF1, MAPK1, RAF1, FGF3, FGF5, GADD45G FGF7, FGF8, FGF10, PDGFB, FGF18, FGF17, FGF19, FGF20, TP53, AKT2, MAP2K2, HRAS, GADD45A, GADD45B hsa04622 RIG-I- 95.04 10 8E-15 1.8E-13 TRAF6, CHUK, NFKB1, RELA, like IKBKG, MAPK8, IKBKB, MAP3K1, receptor MAPK9, MAPK10 signaling MAPK14, pathway MAPK11, MAPK13, MAP3K7 ID Pathway Fold_ occurr lowest_ highest_ Positively_correlat Negatively_correlat Enrich ence p p ed ed ment hsa04015 Rap1 42.8 10 9E-15 7.19E-13 MAPK1, RAF1, MAP2K2, FGF1, signaling RAP1A, FGF9, FGF3, FGF5, pathway FGF16, RAC1, FGF7, FGF8, MAPK14, FGF10, PDGFB, MAPK11, FGF18, FGF17, MAPK13, BRAF, FGF19, FGF20, RAPGEF2, EGFR, FGFR3, CDC42, MRAS, FGFR2, FGFR4, RASGRP2, AKT3 PDGFRA, PDGFRB, RAC2, MAP2K3, MAP2K6, RASGRP3, AKT2, HRAS, RRAS, PRKCA, PRKCG hsa04662 B cell 90.91 10 1E-14 1.21E-11 IKBKG, CHUK, NFKB1, RELA, receptor AKT3, PPP3CA, IKBKB, AKT2, signaling PPP3CB, FOS, JUN, HRAS, pathway PPP3R1, RASGRP3, PPP3R2, RAC1, NFATC1, MAPK1, RAF1, NFATC3, RAC2, SOS1, SOS2, MAP2K2 GRB2 hsa05142 Chagas 63.03 10 2E-14 6.47E-13 TRAF6, MAPK8, MAPK10, FOS, disease MAPK9, JUN, NFKB1, (Americ MAPK14, RELA, IKBKB, an MAPK11, IL1B, TNFRSF1A, trypanos MAPK13, AKT2, TGFB2, omiasis) MAPK1, CHUK, FAS IKBKG, AKT3, TGFB3 hsa04210 Apoptosi 41.28 10 2E-14 1.87E-13 CASP3, AKT3, TP53, NFKB1, s CHUK, IKBKG, RELA, AKT2, GADD45G, IKBKB, NTRK1, MAPK8, MAPK9, TNFRSF1A, FAS, RAF1, MAPK1 GADD45A, GADD45B, DAXX, MAPK10, JUN, FOS, DDIT3, ATF4, HRAS, MAP2K2 hsa05226 Gastric 56.73 10 2E-14 8.05E-11 BRAF, RAF1, HRAS, MAP2K2, cancer MAPK1, GRB2, AKT2, MYC, TP53, SOS1, SOS2, GADD45A, AKT3, GADD45B, GADD45G, TGFB2, FGFR2, TGFB3, FGF9, FGF1, FGF3, FGF16 FGF5, FGF7, FGF8, FGF10, FGF18, FGF17, FGF19, FGF20, EGFR hsa05223 Non- 45.36 10 4E-14 4.36E-12 AKT3, STK4, PRKCA, PRKCG, small SOS1, SOS2, AKT2, HRAS, cell lung GRB2, MAPK1, EGFR, MAP2K2, cancer BRAF, RAF1, TP53, GADD45A, GADD45G GADD45B ID Pathway Fold_ occurr lowest_ highest_ Positively_correlat Negatively_correlat Enrich ence p p ed ed ment hsa04933 AGE- 47.73 10 5E-14 3.46E-12 MAPK8, MAPK9, NFKB1, RELA, RAGE MAPK14, MAPK10, HRAS, signaling MAPK11, TGFB2, IL1B, pathway MAPK13, JUN, AKT2, in MAPK1, TGFB3, NFATC1, PRKCA diabetic CASP3, AKT3, complic CDC42, RAC1 ations hsa05220 Chronic 78.78 10 6E-14 7.33E-13 TGFB3, CHUK, TP53, TGFB2, myeloid IKBKG, SOS1, MYC, NFKB1, leukemi SOS2, GRB2, RELA, IKBKB, a AKT3, MAPK1, AKT2, MAP2K2, BRAF, RAF1, HRAS, GADD45A, GADD45G GADD45B hsa04917 Prolactin 45.45 10 7E-14 6.4E-12 AKT3, MAPK1, AKT2, MAP2K2, signaling RAF1, GRB2, HRAS, MAPK10, pathway SOS1, SOS2, FOS, NFKB1, MAPK8, MAPK9, RELA MAPK14, MAPK11, MAPK13 hsa05131 Shigello 71.98 10 7E-14 1E-13 RAC1, CDC42, IKBKB, NFKB1, sis IKBKG, CHUK, RELA, MAPK10 MAPK8, MAPK9, MAPK1, MAPK14, MAPK11, MAPK13 hsa04510 Focal 23.49 10 9E-14 4.71E-12 CDC42, AKT3, FLNA, FLNB, adhesio RASGRF1, FLNC, AKT2, n MAPK1, BRAF, PRKCA, PRKCG, RAF1, SOS1, ELK1, HRAS, SOS2, GRB2, EGFR, PDGFRA, RAP1A, MAPK8, PDGFRB, PDGFB, MAPK9, PAK1, MAPK10, JUN, PAK2, RAC1 RAC2 hsa04150 mTOR 29.57 10 1E-13 2.22E-10 BRAF, RAF1, HRAS, MAP2K2, signaling MAPK1, AKT3, AKT2, PRKCA, pathway GRB2, SOS1, PRKCG, SOS2, CHUK RPS6KA1, RPS6KA2, RPS6KA3, IKBKB, TNFRSF1A hsa05164 Influenz 33.75 10 2E-13 3.28E-13 ATF2, AKT3, IKBKB, NFKB1, a A MAPK14, RELA, JUN, AKT2, MAPK11, IL1B, MAP2K3, MAPK13, MAP2K6, MAPK8, MAPK9, MAP2K7, HSPA1L, HSPA8, MAPK10, HSPA2, RAF1, MAPK1 HSPA6, PRKCA, MAP2K2, FAS, TNFRSF1A ID Pathway Fold_ occurr lowest_ highest_ Positively_correlat Negatively_correlat Enrich ence p p ed ed ment hsa05222 Small 68.04 10 3E-13 1.08E-09 AKT3, CHUK, AKT2, MYC, cell lung IKBKG, TRAF6, IKBKB, NFKB1, cancer CASP3, RELA, TP53, GADD45G GADD45A, GADD45B hsa04062 Chemok 21.6 10 3E-13 1E-09 GRB2, ARRB1, ARRB2, AKT2, ine CDC42, HRAS, RAC2, signaling RASGRP2, NFKB1, RELA, pathway RAP1A, IKBKB PRKACA, PRKACB, PAK1, MAPK1, AKT3, BRAF, RAF1, RAC1, CHUK, IKBKG, SOS1, SOS2 hsa05133 Pertussi 41.5 10 5E-13 1.1E-09 CASP3, MAPK14, NFKB1, RELA, s MAPK11, IL1B, FOS, JUN, MAPK13, MAPK10, CD14 MAPK1, MAPK8, MAPK9, TRAF6 hsa04540 Gap 57.02 10 6E-13 5.16E-12 MAP3K2, PRKCA, PRKCG, junction PRKACA, MAP2K2, HRAS, PRKACB, EGFR, PDGFRA, MAPK1, RAF1, PDGFRB, PDGFB SOS1, SOS2, GRB2 hsa05213 Endome 94.6 10 6E-13 1.09E-11 SOS1, SOS2, HRAS, ELK1, trial GRB2, AKT3, EGFR, MYC, cancer MAPK1, BRAF, AKT2, MAP2K2, RAF1, GADD45G TP53, GADD45A, GADD45B hsa04072 Phosph 57.3 10 1E-12 2.06E-12 MAPK1, RAF1, MAP2K2, HRAS, olipase RRAS2, MRAS, RRAS, AKT2, D GRB2, SOS1, EGFR, PDGFRA, signaling SOS2, AKT3, PDGFRB, PRKCA, pathway GNA12 PLA2G4A, PDGFB hsa05132 Salmon 49.4 10 1E-12 5.35E-11 RAC1, CDC42, NFKB1, RELA, ella MAPK8, MAPK9, MAPK10, FOS, infection MAPK1, JUN, CD14, FLNA, MAPK14, FLNB, FLNC, IL1B MAPK11, MAPK13 hsa04370 VEGF 62.09 10 1E-12 2.13E-10 CDC42, PPP3CA, PLA2G4A, HSPB1, signaling PPP3CB, MAPKAPK3, pathway PPP3R1, MAPKAPK2, PPP3R2, AKT3, AKT2, PRKCA, MAPK14, PRKCG, MAP2K2, MAPK11, HRAS, RAC2 MAPK13, MAPK1, RAF1, RAC1 ID Pathway Fold_ occurr lowest_ highest_ Positively_correlat Negatively_correlat Enrich ence p p ed ed ment hsa05221 Acute 46.78 10 2E-12 8.78E-11 CHUK, IKBKG, MYC, NFKB1, myeloid SOS1, SOS2, RELA, HRAS, leukemi GRB2, AKT3, IKBKB, AKT2, a MAPK1, BRAF, MAP2K2, CD14, RAF1 DUSP6 hsa05140 Leishma 77.13 10 2E-12 9.52E-10 TGFB3, MAPK1, NFKB1, RELA, niasis MAPK14, TGFB2, IL1B, MAPK11, ELK1, FOS, JUN MAPK13, TRAF6, TAB1, TAB2, MAP3K7 hsa04218 Cellular 45.61 10 2E-12 4E-12 AKT3, RRAS2, MYC, TP53, AKT2, senesce MRAS, RAF1, HRAS, RRAS, nce MAPK1, MAP2K2, MAPK14, MAP2K3, MAPK11, MAP2K6, MAPK13, GADD45A, GADD45G, GADD45B, PPP3CA, NFKB1, RELA, PPP3CB, MAPKAPK2, PPP3R1, NFATC1, PPP3R2, TGFB3 NFATC3, TGFB2 hsa05230 Central 49.9 10 3E-12 2E-11 RAF1, MAPK1, MYC, EGFR, carbon AKT3 FGFR3, FGFR2, metaboli NTRK1, PDGFRA, sm in PDGFRB, HRAS, cancer MAP2K2, AKT2, TP53 hsa04914 Progest 42.65 10 3E-12 5E-09 MOS, AKT3, AKT2, CDC25B, erone- PRKACA, RPS6KA1, mediate PRKACB, RPS6KA2, d oocyte MAPK1, RPS6KA3, maturati MAPK14, MAPK10 on MAPK8, MAPK11, MAPK9, MAPK13, BRAF, RAF1 hsa04920 Adipocyt 64.38 10 4E-12 1.07E-08 CHUK, IKBKG, NFKB1, RELA, okine MAPK8, MAPK9, IKBKB, MAPK10, signaling AKT3 AKT2, TNFRSF1A pathway hsa04720 Long- 49.9 10 4E-12 1.78E-09 PPP3CA, PRKCA, PRKCG, term PPP3CB, RPS6KA1, potentiat PPP3R1, RPS6KA2, ion PPP3R2, RPS6KA3, ATF4, PRKACA, MAP2K2, HRAS PRKACB, CACNA1C, MAPK1, BRAF, RAF1, RAP1A ID Pathway Fold_ occurr lowest_ highest_ Positively_correlat Negatively_correlat Enrich ence p p ed ed ment hsa04928 Parathyr 45.53 10 8E-12 3.27E-09 PRKACA, ARRB2, PRKCA, oid PRKACB, PRKCG, EGFR, hormon ARRB1, BRAF, ATF4, FOS, JUND, e RAF1, MAPK1, MEF2C synthesi GNA12, ATF2 s, secretio n and action hsa04024 cAMP 43.33 10 1E-11 4.32E-10 CACNA1C, CACNA1S, AKT2, signaling CACNA1F, MAP2K2, pathway PRKACA, MAPK10, NFKB1, PRKACB, AKT3, RELA, NFATC1, MAPK1, RAP1A, RRAS, BDNF, RAF1, BRAF, FOS, JUN, RAC2 MAPK8, MAPK9, RRAS2, RAC1, PAK1 hsa04071 Sphingol 39.03 10 1E-11 5.95E-10 MAPK1, RAF1, MAP2K2, AKT2, ipid AKT3, GNA12, PRKCA, PRKCG, signaling MAPK8, MAPK9, HRAS, MAPK10, pathway MAPK14, TP53, NFKB1, MAPK11, RELA, RAC2, MAPK13, RAC1 TNFRSF1A hsa05211 Renal 82.96 10 1E-11 1.4E-09 TGFB3, RAC1, TGFB2, PDGFB, cell SOS1, SOS2, AKT2, JUN, carcino GRB2, PAK1, MAP2K2, HRAS ma PAK2, RAP1A, CDC42, AKT3, MAPK1, BRAF, RAF1 hsa04140 Autopha 50.1 10 2E-11 2.77E-11 AKT3, RRAS2, AKT2, HRAS, gy - MRAS, RAF1, RRAS, MAP2K2, animal MAPK1, MAPK10 MAP3K7, MAPK8, MAPK9, PRKACA, PRKACB, TRAF6 hsa05162 Measles 26.4 10 3E-11 5.26E-10 AKT3, HSPA1L, NFKB1, RELA, HSPA8, CHUK, AKT2, HSPA2, TRAF6, MAP3K7, HSPA6, IL1B, TAB2 FAS, TP53 hsa04310 Wnt 35.41 10 5E-11 8.29E-11 PPP3CA, NFATC1, signaling PPP3CB, NFATC3, PRKCA, pathway PPP3R1, PRKCG, MAPK10, PPP3R2, MAPK8, RAC2, JUN, MYC, MAPK9, RAC1, TP53 NLK, MAP3K7, PRKACA, PRKACB hsa05165 Human 14.15 10 5E-11 5.43E-09 AKT3, CHUK, AKT2, EGFR, papillom IKBKG, GRB2, TP53, IKBKB, avirus SOS1, SOS2, NFKB1, RELA, infection RAF1, MAPK1, HRAS, MAP2K2, CASP3, CDC42, TNFRSF1A, FAS, PRKACA, PDGFRB PRKACB ID Pathway Fold_ occurr lowest_ highest_ Positively_correlat Negatively_correlat Enrich ence p p ed ed ment hsa04919 Thyroid 27.47 10 7E-11 1.34E-08 AKT3, RAF1, AKT2, PRKCA, hormon PRKACA, PRKCG, HRAS, e PRKACB, MAPK1 MAP2K2, TP53, signaling MYC pathway hsa04213 Longevit 46.69 10 9E-11 5.76E-09 AKT3, PRKACA, AKT2, HRAS, y PRKACB, HSPA2, HSPA6 regulatin HSPA1L, HSPA8 g pathway - multiple species hsa05225 Hepatoc 40.54 10 1E-10 1.9E-10 BRAF, RAF1, EGFR, HRAS, ellular MAPK1, GRB2, MAP2K2, AKT2, carcino SOS1, SOS2, MYC, TP53, ma AKT3, GADD45A, GADD45G, GADD45B, TGFB3 PRKCA, PRKCG, ELK1, TGFB2 hsa05203 Viral 33.45 10 1E-10 7.38E-09 CASP3, IKBKG, TP53, JUN, ATF4, carcinog MAPK1, ATF2, NFKB1, NFKB2, enesis RASA2, CDC42, RELA, SRF, RAC1, PRKACA, HRAS, PRKACB, GRB2 MAPKAPK2 hsa05216 Thyroid 72.97 10 1E-10 7.42E-09 BRAF, MAPK1, HRAS, MAP2K2, cancer GADD45G MYC, NTRK1, TP53, GADD45A, GADD45B hsa05152 Tubercul 27.44 10 1E-10 4.95E-10 RAF1, PPP3CA, NFKB1, RELA, osis PPP3CB, CD14, TNFRSF1A, PPP3R1, AKT2, IL1B, PPP3R2, MAPK1, MAPK10, TGFB2 TRAF6, CASP3, AKT3, MAPK8, MAPK9, MAPK14, MAPK11, MAPK13, TGFB3 hsa04728 Dopami 23.67 10 4E-10 4.92E-08 PRKACA, PRKCA, PRKCG, nergic PRKACB, CACNA1B, AKT2, synapse CACNA1A, AKT3, ATF4, MAPK10, ATF2, MAPK14, FOS, ARRB2 MAPK8, MAPK11, MAPK9, MAPK13, PPP3CA, PPP3CB, CACNA1C ID Pathway Fold_ occurr lowest_ highest_ Positively_correlat Negatively_correlat Enrich ence p p ed ed ment hsa04910 Insulin 22.3 10 5E-10 2.94E-08 MAPK8, MAPK9, IKBKB, MAPK10, signaling MKNK1, MAPK1, ELK1, MKNK2, pathway PRKACA, HRAS, MAP2K2, PRKACB, SOS1, AKT2 SOS2, GRB2, BRAF, RAF1, AKT3 hsa04650 Natural 27.27 10 6E-10 1.39E-09 PPP3CA, NFATC1, PRKCA, killer cell PPP3CB, PRKCG, FAS, mediate PPP3R1, MAP2K2, HRAS, d PPP3R2, CASP3, RAC2 cytotoxic MAPK1, BRAF, ity RAF1, SOS1, SOS2, GRB2, PAK1, RAC1 hsa04630 Jak- 24.22 10 9E-10 2.76E-07 AKT3, SOS1, MYC, AKT2, STAT SOS2, GRB2, EGFR, PDGFRA, signaling RAF1 PDGFRB, HRAS, pathway PDGFB hsa04137 Mitopha 47.99 10 1E-09 2.15E-08 RRAS2, MRAS, ATF4, RELA, gy - MAPK8, MAPK9 TP53, HRAS, animal RRAS, MAPK10, JUN hsa04371 Apelin 44.94 10 1E-09 2.19E-09 AKT3, MAPK1, AKT2, MAP2K2, signaling RRAS2, MRAS, HRAS, RRAS, pathway RAF1, PRKACA, MEF2C PRKACB hsa04932 Non- 36.68 10 3E-09 9.61E-08 AKT3, CASP3, AKT2, NFKB1, alcoholic MAPK8, MAPK9, RELA, FAS, ATF4, fatty CDC42, RAC1 DDIT3, JUN, liver MAPK10, IKBKB, disease IL1B, MAP3K11, (NAFLD TNFRSF1A ) hsa04261 Adrener 21.21 10 6E-09 1.29E-07 CACNA1C, CACNA1S, gic CACNA1F, CACNB2, signaling CACNA2D1, CACNG5, in CACNB1, CACNG4, AKT2, cardiom CACNB3, ATF4, PRKCA yocytes CACNG1, CACNA2D2, CACNG3, CACNG2, PRKACA, PRKACB, AKT3, MAPK1, ATF2, MAPK14, MAPK11, MAPK13, RPS6KA5 ID Pathway Fold_ occurr lowest_ highest_ Positively_correlat Negatively_correlat Enrich ence p p ed ed ment hsa05206 MicroRN 25.59 10 6E-09 2.62E-08 STMN1, CASP3, CDC25B, EGFR, As in MAPK1, GRB2, TGFB2, MYC, cancer RPS6KA5, RAF1, HRAS, NFKB1, SOS1, SOS2 IKBKB, PRKCA, PRKCG, FGFR3, TP53, PDGFRA, MAP2K2, PDGFB, PDGFRB hsa04723 Retrogra 21.03 10 6E-09 4.31E-05 CACNA1A, PRKCA, PRKCG, de CACNA1C, CACNA1B, endocan CACNA1F, CACNA1S, nabinoid PRKACA, MAPK10 signaling PRKACB, MAPK14, MAPK1, MAPK8, MAPK11, MAPK9, MAPK13 hsa04115 p53 45.03 10 1E-08 0.00059 GADD45G, GADD45A, signaling CASP3 GADD45B, FAS, pathway TP53 hsa04750 Inflamm 28.55 10 1E-08 1.73E-07 PRKACA, IL1R1, NTRK1, atory PRKACB, IL1B, PLA2G4A, mediator MAPK14, MAPK10, PRKCA, regulatio MAPK8, PRKCG, MAP2K3, n of MAPK11, MAP2K6 TRP MAPK9, MAPK13 channel s hsa04211 Longevit 48.68 10 2E-08 1.89E-06 AKT3, PRKACA, AKT2, HRAS, y PRKACB, ATF2 ATF4, TP53, regulatin NFKB1, RELA g pathway hsa04022 cGMP- 22.01 10 2E-08 0.00018 CACNA1C, CACNA1S, PKG CACNA1F, NFATC1, signaling PPP3CA, NFATC3, MEF2C, pathway PPP3CB, SRF, MAP2K2, PPP3R1, ATF4, AKT2 PPP3R2, RAF1, MAPK1, ATF2, AKT3, GNA12 ID Pathway Fold_ occurr lowest_ highest_ Positively_correlat Negatively_correlat Enrich ence p p ed ed ment hsa04921 Oxytocin 33.87 10 3E-08 5.36E-07 PRKACA, PRKCA, PRKCG, signaling PRKACB, RAF1, HRAS, MAP2K2, pathway MAPK1, PLA2G4A, CACNA1C, CACNA1S, CACNA1F, CACNB2, CACNA2D1, CACNG5, CACNB1, CACNG4, CACNB3, NFATC1, CACNG1, NFATC3, JUN, CACNA2D2, FOS, MEF2C, CACNG3, ELK1, EGFR CACNG2, PPP3CA, PPP3CB, PPP3R1, PPP3R2 hsa04066 HIF-1 45.45 10 3E-08 4.22E-05 AKT3, MAPK1, EGFR, AKT2, signaling MKNK1 PRKCA, PRKCG, pathway NFKB1, RELA, MAP2K2, MKNK2 hsa04730 Long- 72.67 10 6E-08 8.25E-08 GNA12, PLA2G4A, term CACNA1A, PRKCA, PRKCG, depressi MAPK1, BRAF, MAP2K2, HRAS on RAF1 hsa04931 Insulin 35.56 10 6E-08 5.18E-06 MAPK8, MAPK9, MAPK10, resistan AKT3 TNFRSF1A, ce IKBKB, AKT2, NFKB1, RELA, RPS6KA1, RPS6KA2, RPS6KA3 hsa04934 Cushing' 37.27 10 6E-08 1.9E-07 CACNA1C, CACNA1S, s CACNA1F, CACNA1I, ATF4, syndrom CACNA1H, ATF2, NR4A1, EGFR, e PRKACA, MAP2K2 PRKACB, MAPK1, RAP1A, BRAF hsa04520 Adheren 40.32 10 7E-08 2.35E-05 NLK, MAP3K7, EGFR, RAC2 s MAPK1, RAC1, junction CDC42 hsa04144 Endocyt 17.66 10 1E-07 1.81E-06 TRAF6, HSPA1L, HSPA2, HSPA6, osis HSPA8, CDC42, HRAS, EGFR, ARRB1 FGFR3, FGFR2, FGFR4, PDGFRA, ARRB2 hsa04623 Cytosoli 61.6 10 1E-07 2.7E-07 CHUK, IKBKG IL1B, NFKB1, c DNA- RELA, IKBKB sensing pathway hsa05030 Cocaine 63.63 10 1E-07 5.42E-06 PRKACA, JUN, NFKB1, addictio PRKACB, ATF2 RELA, ATF4, n BDNF ID Pathway Fold_ occurr lowest_ highest_ Positively_correlat Negatively_correlat Enrich ence p p ed ed ment hsa04141 Protein 23.72 10 1E-07 1.72E-07 MAPK8, MAPK9, ATF4, DDIT3, processi HSPA1L, HSPA8 MAPK10, ng in MAP2K7, HSPA2, endopla HSPA6 smic reticulu m hsa04930 Type II 55.44 10 1E-07 1.72E-07 MAPK1, MAPK8, IKBKB, MAPK10, diabetes MAPK9, CACNA1B mellitus CACNA1A, CACNA1C, CACNA1E hsa05134 Legionel 54.21 10 2E-07 4.05E-07 CASP3, HSPA1L, IL1B, NFKB1, losis HSPA8 RELA, NFKB2, HSPA2, HSPA6, CD14 hsa04550 Signalin 34.85 10 2E-07 4.06E-06 AKT3, GRB2, AKT2, HRAS, g MAPK1, RAF1, MAP2K2, FGFR3, pathway MAPK14, FGFR2, FGFR4, s MAPK11, MYC, DUSP9 regulatin MAPK13 g pluripote ncy of stem cells hsa05014 Amyotro 48.79 10 2E-07 2.79E-07 CASP3, MAPK14, TNFRSF1A, phic MAPK11, DAXX, MAP2K3, lateral MAPK13, RAC1, MAP2K6, TP53 sclerosis PPP3CA, (ALS) PPP3CB, PPP3R1, PPP3R2 hsa05031 Amphet 32.72 10 3E-07 4.9E-07 CACNA1C, ATF4, PRKCA, amine PRKACA, PRKCG, FOS, addictio PRKACB, ATF2, JUN n PPP3CA, PPP3CB, PPP3R1, PPP3R2 hsa04530 Tight 17.45 10 3E-07 1.54E-05 CDC42, RAC1, MAP2K7, junction RAP1A, MAPK10, PRKACA, MAP3K1, JUN PRKACB, MAPK8, MAPK9, RAPGEF2 hsa04270 Vascular 22.42 10 4E-07 2E-05 GNA12, PRKCA, PRKCG, smooth CACNA1C, CACNA1S, muscle CACNA1F, PLA2G4A, contracti BRAF, RAF1, MAP2K2 on MAPK1, PRKACA, PRKACB ID Pathway Fold_ occurr lowest_ highest_ Positively_correlat Negatively_correlat Enrich ence p p ed ed ment hsa04726 Seroton 54.45 10 4E-07 4.72E-06 PRKACA, PRKCA, PRKCG, ergic PRKACB, CACNA1B, synapse CACNA1A, PLA2G4A, CACNA1C, CACNA1S, CACNA1F, DUSP1, HRAS CASP3, MAPK1, BRAF, RAF1 hsa05202 Transcri 21.29 10 5E-07 4.67E-05 ELK4, GADD45G DDIT3, MYC, ptional CD14, MEF2C, misregul TP53, NTRK1, ation in DUSP6, NFKB1, cancer RELA, GADD45A, GADD45B hsa05217 Basal 27.33 10 8E-07 0.00999 GADD45G TP53, GADD45A, cell GADD45B carcino ma hsa04666 Fc 19.8 10 1E-06 4.2E-05 RAF1, MAPK1, PLA2G4A, AKT2, gamma AKT3, RAC1, RAC2, PRKCA, R- CDC42, PAK1 PRKCG mediate d phagocy tosis hsa05146 Amoebi 39.13 10 2E-06 2.09E-05 CASP3, IL1B, NFKB1, asis PRKACA, RELA, IL1R1, PRKACB, TGFB3 HSPB1, CD14, PRKCA, PRKCG, TGFB2 hsa04725 Choliner 20.79 10 3E-06 1.58E-05 PRKACA, PRKCA, PRKCG, gic PRKACB, CACNA1B, ATF4, synapse CACNA1A, AKT2, CACNA1S, MAPK1, AKT3, HRAS, FOS CACNA1C, CACNA1F hsa05034 Alcoholi 15.37 10 4E-06 7.89E-05 PRKACA, ATF2, ATF4, BDNF, sm BRAF, RAF1, HRAS MAPK1, NTRK2, GRB2, SOS1, SOS2 hsa04215 Apoptosi 53.81 10 5E-06 8.13E-05 CASP3, MAPK8, TNFRSF1A, s - MAPK9 MAPK10 multiple species hsa04110 Cell 21.81 10 5E-06 0.00029 GADD45G, GADD45A, cycle TGFB3 GADD45B, TP53, TGFB2, CDC25B, MYC hsa04670 Leukocy 32 10 5E-06 0.00251 MAPK14, PRKCA, PRKCG, te MAPK11, RAC2 transend MAPK13, RAC1, othelial RAP1A, CDC42 migratio n ID Pathway Fold_ occurr lowest_ highest_ Positively_correlat Negatively_correlat Enrich ence p p ed ed ment hsa05321 Inflamm 48.91 10 6E-06 0.00053 TGFB3 NFKB1, RELA, atory TGFB2, NFATC1, bowel IL1B, JUN disease (IBD) hsa04611 Platelet 29.31 10 8E-06 0.00112 RASGRP2, AKT2, PLA2G4A activatio RAP1A, AKT3, n MAPK14, MAPK11, MAPK13, MAPK1, PRKACA, PRKACB hsa04916 Melanog 51.63 10 8E-06 3.59E-05 PRKACA, PRKCA, PRKCG, enesis PRKACB, MAP2K2, HRAS MAPK1, RAF1 hsa04360 Axon 26.93 10 9E-06 2.83E-05 MAPK1, RAC1, RAC2, NFATC3, guidanc PPP3CA, HRAS, PRKCA, e PPP3CB, RRAS PPP3R1, PPP3R2, CDC42, PAK1, PAK2, RASA1, RAF1 hsa04612 Antigen 26.4 10 1E-05 1.84E-05 HSPA1L, HSPA8 HSPA2, HSPA6 processi ng and presenta tion hsa04918 Thyroid 28.19 10 1E-05 0.00018 PRKACA, PRKCA, PRKCG, hormon PRKACB, ATF2 ATF4 e synthesi s hsa04714 Thermo 13.54 10 1E-05 0.00015 PRKACA, RPS6KA1, genesis PRKACB, RPS6KA2, MAPK14, RPS6KA3, HRAS, MAPK11, MAP2K3 MAPK13, ATF2, GRB2, SOS1, SOS2 hsa04911 Insulin 24.82 10 2E-05 0.00025 CACNA1C, CACNA1S, secretio CACNA1F, PRKCA, PRKCG, n PRKACA, ATF4 PRKACB, ATF2 hsa05032 Morphin 19.86 10 3E-05 0.00053 PRKACA, CACNA1B, e PRKACB, PRKCA, PRKCG, addictio CACNA1A, ARRB2 n ARRB1 hsa05020 Prion 41.58 10 3E-05 0.00034 PRKACA, MAP2K2, ELK1, disease PRKACB, MAPK1 IL1B s hsa04713 Circadia 20.79 10 3E-05 7.51E-05 CACNA1H, PRKCA, PRKCG, n MAPK1, CACNA1I, FOS entrainm PRKACA, ent PRKACB, CACNA1C, RPS6KA5 ID Pathway Fold_ occurr lowest_ highest_ Positively_correlat Negatively_correlat Enrich ence p p ed ed ment hsa04925 Aldoster 21.88 10 3E-05 7.51E-05 CACNA1C, CACNA1S, one CACNA1F, CACNA1I, ATF4, synthesi CACNA1H, ATF2, PRKCA, PRKCG, s and PRKACA, NR4A1 secretio PRKACB n hsa04020 Calcium 13.86 10 4E-05 0.00016 PPP3CA, PRKCA, PRKCG, signaling PPP3CB, EGFR, PDGFRA, pathway PPP3R1, PDGFRB, PPP3R2, CACNA1S, CACNA1C, CACNA1B, CACNA1F, CACNA1I CACNA1A, CACNA1E, PRKACA, PRKACB, CACNA1H hsa04961 Endocri 30.94 10 4E-05 0.0012 PRKACA, PRKCA, PRKCG ne and PRKACB other factor- regulate d calcium reabsor ption hsa04922 Glucago 18.9 10 4E-05 0.00085 PRKACA, ATF4, AKT2 n PRKACB, ATF2, signaling AKT3, PPP3CA, pathway PPP3CB, PPP3R1, PPP3R2 hsa04923 Regulati 28.92 10 6E-05 0.00166 PRKACA, AKT2 on of PRKACB, AKT3 lipolysis in adipocyt es hsa04114 Oocyte 16.8 10 0.0001 0.0013 MOS, MAPK1, RPS6KA1, meiosis PPP3CA, RPS6KA2, PPP3CB, RPS6KA3 PPP3R1, PPP3R2, PRKACA, PRKACB hsa05416 Viral 82.85 9 0.00012 0.00012 CASP3, RAC1 RAC2 myocard itis hsa04340 Hedgeh 33.26 10 0.00014 0.00071 PRKACA, ARRB2 og PRKACB, ARRB1 signaling pathway ID Pathway Fold_ occurr lowest_ highest_ Positively_correlat Negatively_correlat Enrich ence p p ed ed ment hsa05010 Alzheim 29.13 10 0.00017 0.00172 CASP3, CACNA1S, FAS, er's CACNA1C, TNFRSF1A, IL1B disease CACNA1F, MAPT, MAPK1, PPP3CA, PPP3CB, PPP3R1, PPP3R2 hsa04971 Gastric 24.64 10 0.00021 0.00434 PRKACA, PRKCA, PRKCG acid PRKACB secretio n hsa04973 Carbohy 48.07 10 0.00023 0.02095 AKT3 AKT2 drate digestio n and absorpti on hsa04727 GABAer 20.16 10 0.00038 0.00681 CACNA1A, CACNA1B, gic PRKACA, CACNA1S, synapse PRKACB, PRKCA, PRKCG CACNA1C, CACNA1F hsa04927 Cortisol 38.18 10 0.0004 0.00053 CACNA1C, CACNA1S, synthesi CACNA1F, CACNA1I, ATF4, s and CACNA1H, ATF2, NR4A1 secretio PRKACA, n PRKACB hsa04970 Salivary 21.81 10 0.00041 0.0072 PRKACA, PRKCA, PRKCG secretio PRKACB n hsa04724 Glutama 35.24 10 0.00041 0.00082 CACNA1C, PRKCA, PRKCG, tergic PRKACA, PLA2G4A synapse PRKACB, PPP3CA, PPP3CB, PPP3R1, PPP3R2, CACNA1A, MAPK1 hsa03040 Spliceos 15.37 10 0.00043 0.0005 HSPA1L, HSPA8 HSPA2, HSPA6 ome hsa05323 Rheuma 15.52 10 0.00046 0.00853 TGFB3 IL1B, TGFB2, toid FOS, JUN arthritis hsa04960 Aldoster 41 10 0.00085 0.00385 MAPK1 PRKCA, PRKCG one- regulate d sodium reabsor ption hsa04217 Necropt 12.21 10 0.00088 0.00191 MAPK8, MAPK9 TNFRSF1A, FAS, osis IL1B, MAPK10, PLA2G4A ID Pathway Fold_ occurr lowest_ highest_ Positively_correlat Negatively_correlat Enrich ence p p ed ed ment hsa05414 Dilated 50.82 10 0.00093 0.00164 CACNA1C, CACNA1S, cardiom CACNA1F, CACNB2, yopathy CACNA2D1, CACNG5, (DCM) CACNB1, CACNG4, TGFB2 CACNB3, CACNG1, CACNA2D2, CACNG3, CACNG2, PRKACA, PRKACB, TGFB3 hsa04350 TGF- 24.06 10 0.00095 0.0012 MAPK1, TGFB3 MYC, TGFB2 beta signaling pathway hsa05340 Primary 107.6 3 0.00108 0.00108 IKBKG immuno deficien cy hsa05412 Arrhyth 63.09 10 0.00111 0.01738 CACNA1C, CACNA1S, mogenic CACNA1F, CACNB2, right CACNA2D1, CACNG5, ventricul CACNB1, CACNG4 ar CACNB3, cardiom CACNG1, yopathy CACNA2D2, (ARVC) CACNG3, CACNG2 hsa05110 Vibrio 23.76 10 0.00116 0.00314 PRKACA, PRKCA cholerae PRKACB infection hsa04260 Cardiac 62.02 10 0.00123 0.0184 CACNA1C, CACNA1S, muscle CACNA1F, CACNB2, contracti CACNA2D1, CACNG5, on CACNB1, CACNG4 CACNB3, CACNG1, CACNA2D2, CACNG3, CACNG2 hsa05410 Hypertro 52.27 10 0.00132 0.00563 CACNA1C, CACNA1S, phic CACNA1F, CACNB2, cardiom CACNA2D1, CACNG5, yopathy CACNB1, CACNG4, TGFB2 (HCM) CACNB3, CACNG1, CACNA2D2, CACNG3, CACNG2, TGFB3 hsa04392 Hippo 64.19 10 0.0022 0.0043 PAK1 STK3 signaling pathway - multiple species ID Pathway Fold_ occurr lowest_ highest_ Positively_correlat Negatively_correlat Enrich ence p p ed ed ment hsa04913 Ovarian 59.74 10 0.00262 0.00415 PRKACA, PLA2G4A steroido PRKACB genesis hsa04120 Ubiquitin 18.34 10 0.00344 0.00393 TRAF6 MAP3K1 mediate d proteoly sis hsa04390 Hippo 27.1 10 0.00367 0.00459 TGFB3 STK3, TGFB2, signaling MYC, FGF1 pathway hsa04152 AMPK 8.99 10 0.00392 0.03459 AKT3, MAP3K7 AKT2 signaling pathway hsa05143 African 59.14 10 0.00415 0.01382 IL1B, FAS, trypanos PRKCA, PRKCG omiasis hsa05100 Bacterial 28.25 10 0.00448 0.01955 RAC1, CDC42 invasion of epithelial cells hsa05332 Graft- 55.76 5 0.00533 0.00533 FAS, IL1B versus- host disease hsa04962 Vasopre 22.18 10 0.00553 0.01487 PRKACA, ssin- PRKACB regulate d water reabsor ption hsa04940 Type I 51.35 5 0.00563 0.00563 FAS, IL1B diabetes mellitus hsa04924 Renin 26.09 10 0.00584 0.01351 PRKACA, CACNA1S secretio PRKACB, n CACNA1C, CACNA1F, PPP3CA, PPP3CB, PPP3R1, PPP3R2 hsa04060 Cytokine 13.74 10 0.00642 0.0216 TGFB3 IL1R1, IL1B, - TGFB2, FAS, cytokine TNFRSF1A receptor interacti on hsa04976 Bile 18.1 10 0.01029 0.03295 PRKACA, secretio PRKACB n ID Pathway Fold_ occurr lowest_ highest_ Positively_correlat Negatively_correlat Enrich ence p p ed ed ment hsa04972 Pancrea 28.64 10 0.01035 0.02771 RAP1A, RAC1 PRKCA, PRKCG tic secretio n hsa04742 Taste 19.71 10 0.01289 0.04213 CACNA1A, transduc CACNA1C, tion PRKACA, PRKACB hsa05144 Malaria 15.15 7 0.01534 0.0275 TGFB3 TGFB2, IL1B hsa05130 Pathoge 20.85 10 0.01744 0.02154 CDC42 CD14, PRKCA nic Escheric hia coli infection hsa05016 Huntingt 11.63 3 0.01832 0.02939 CASP3 BDNF, TP53 on's disease hsa04145 Phagos 21.52 9 0.02202 0.02202 RAC1 CD14 ome hsa05012 Parkinso 21.24 7 0.02495 0.0293 CASP3, n's PRKACA, disease PRKACB hsa03450 Non- 152.5 1 0.04809 0.04809 homolog ous end- joining