CST SIGNALING PATHWAY DIAGRAMS FOR Cellular Metabolism

Insulin Receptor Signaling © 2003–2015 Cell Signaling Technology, Inc. Insulin Receptor SNARE TNF Glucose Complex GLUT4 p85 FlotillinCav

PTEN PI3K Gab1 p110 SOCS3

Synip CAP TNFR1 Cbl

PIP3 IRS Shc APS SHIP Akt2 SHP-2 PTP1B GLUT4 Crkll EHD1 GRB2 Nck Translocation TC10 C3G EHBP1 IRS-1 Crkll λ/ζ CIP4/2 PKC Fyn SOS PDK1 Rac1 mTORC2 PKCθ GRB10 Jnk GLUT4 PKCλ/ζ IKK vesicle Ras PP2A FFA 14-3-3 LKB1 NO iNOS GLUT4 AS160 Exocytosis Akt ROS c-Raf TBC1D1 AMPK PDK1 14-3-3 TSC2 PDE3B TSC1 Bad SIK2 GSK-3 PRAS40 Rheb [cAMP] MEK1/2 SGK Apoptosis SREBP CBP/p300 mTORC1 PKA Torc2 p70 Erk1/2 PP1 GS Lipin1 4E-BP1 S6K ATP-citrate Degradation ENaC lyase eIF4E HSL Glycogen Synthesis Protein Synthesis, Fatty Acid Growth, and SREBP-1 Sodium Synthesis Proliferation Lipolysis Transport

Cytoplasm Erk1/2 SGK Akt2 Fatty Acid and Cholesterol Disruption of Nucleus Synthesis CBP/Torc2/CREB Complex FoxO3 FoxO4 FoxO1 Erk1/2 SREBP LXRα USF Gluconeogenesis Transcription Apoptosis, mTORC1 mTORC2 Autophagy, Lipin1 Glucose and Raptor Sin1 PRR5 GβL Lipid Metabolism Growth mTOR Rictor GβL DEPTOR mTOR DEPTOR

Warburg Effect © 2010–2015 Cell Signaling Technology, Inc. Macropinocytosis and other scavenging pathways Glycolysis Growth Factors Glucose Glucose Transporters

Ras Hexokinase PI3K Amino Acids NADPH NADP Ras Pentose and Lipids c-Myc Phosphate 6-P- Glucose-6-P Akt Shunt Gluconolactone 6-P- MEK1/2 NADP Ras Amino Acids Gluconate TIGAR Fructose-6-P NADPH p53 LKB1 SREBP PFK Erk1/2 Ribulose-5P AMPK Fructose mTOR Bisphosphate Nucleotide c-Myc HIF-1α Synthesis PHGDH Serine 3-Phosphoglycerate Protein Synthesis Cell Proliferation NADPH c-Myc NADP Glycine PEP ULK1 PKM2 HIF-1α Fatty Acid Oxidation NADP c-Myc Pyruvate Autophagy Fatty Acids NADPH Malic Enzyme LDHA Pyruvate PDHK Lactate Dehydrogenase Malate Pyruvate Acetyl-CoA Folate β Metabolism Oxaloacetate -Oxidation Acetate

Bax Akt ANT Krebs Malate Cycle Citrate Citrate ACSS2 Hexokinase VDAC ACL ANT UCP2 IDH2 AMPK Acetyl-CoA VDAC α-Ketoglutarate IDH1 ACC OMM Stability Fatty Acid/ NADP Inhibition Cytochrome C Release Glutaminase Lipid Synthesis Inhibition of Apoptosis NADPH Epigenetic p53 Glutamine Transporters Regulation

Glutamine AMPK Signaling Glutaminolysis © 2008–2015 Cell Signaling Technology, Inc.

Low Glucose, Hypoxia, Ischemia, Heat Shock Brain AICAR Insulin Leptin Exercise α-Adrenergic Histamine Other RTKs Receptor Adiponectin Receptor Thrombin Glucose Receptor Glut1 Insulin Glut4

PLCβ Gα q [cAMP] AMP + ADP ATP Glut1 vesicle PKA Ras [Ca2+] PI3K Glut Glut Translocation STRAD B-Raf Trafficking CaMKK LKB1 MO25α

Glut4

vesicle TXNIP Erk Akt

A

c u

t Glycogen TBC1D1 e GS p90RSK γ R Synthesis β

e

g

u TSC2 l Glycolysis PFKFB3 α a AMPK y

t g

i

o

TSC1 Rheb a

n

h

HMG-CoA p o

o f t Sterol/Isoprenoid Reductase M ACC Raptor u

e Synthesis A

t β d a Malonyl mTOR G L

b n

CoA a o

l i CPT1 s m

m s i ULK1 4E-BP1 l Fatty Acid p70 o b

a Oxidation HSL FIP200 ATG13 S6K t e

Autophagy M

n i e p300 t Beclin o r ATGL SREBP-1 P PI3K Lipolysis Atg14 MYPT1 Class III Tau MBS85 HNF4α SirT1 HDAC4 Fatty Acid CLIP170 Synthase HDAC5 Microtubules Lipogenesis HDAC7 TORC2/ Myosin CRTC2 C Light yt Chain2 os ke PGC1α m le Actin lis ta o l S Dynamics ab ig CREB et n M ali of ng CRY1 ol FoxO Gluconeogenesis ntr Co nal ptio scri Tran

Direct Stimulatory Multistep Inhibitory Separation of Subunits Transcriptional Receptor GTPase Modification Modification or Cleavage Products Inhibitory Modification Enzyme G-protein Direct Inhibitory Tentative Stimulatory Joining of Subunits Kinase pro-apoptotic Acetylase Modification Modification Translocation Phosphatase pro-survival Deacetylase Multistep Stimulatory Tentative Inhibitory Transcriptional Transcription Factor Modification Modification GAP/GEF Stimulatory Modification Ribosomal subunit Caspase

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