A Canonical Cancer-Network Map Eugene F. Douglass Jr., Ph.D. ;<=:>&'? Cell-Surface Interactions @@@JJ; Growth Receptor Signalling Cell-ECM Growth/Motility Proliferation Cell-Cell Contact Inhibition Metabolism MMP COLONIC CRYPT IGF/IGFR-1 EGFR / ErbB WNT ! WNT ! WNT WNT Integrin WNT RAS must be held near PI3K to activate it 5 CAD-domains Signalosome R-spdn p.195 GTP RAS PTEN NF1 SOS PLC PIP3 E-cadherin SHC PIP RASGAP GRB2 2 ZNRF3 p120 p120 " p120 p120 p120 p120 FZD Akt PDK1 PH JM Src-dep Y845 STAT3 GDP GTP Y974 F-actin PI3K PTB SHC/SHP2 GRB2 LRP Assembly vincilin talin PI3K Integrin-Linked Kinase(ILK) Y981 RAS RAS LGR RNF43 NCK2 ! ! ! ARP2/3 FAK Y988 FAK 2 min PINCH SOCS3 C hevell Akt KD s e paxilin SOS i d PDK1 Src IRS1 ! ! ! d paxilin Src (PKB) internlz AP2 RSU1 Y1015 ½ HIC5 ! t PI3K Y460 SOCS1/6 Y992 PLC" Parvin Src TESK1 PI3K Y546 SHIP2 GTP p130Cas CRK CSG ubiq axin PAK1 Y1091 Y1045 CBL S46-7 RAF-1 KSR DOCK180 SOS PI3K Y608 S1057 = GSK3 PI3K Y628 Y1127 Y1068 GRB2 14-3-3 14-3-3 PI3K Y658 GRB2 Y1086 B-RAF C-RAF GSK RHEB PI3K Y690 RASGAP 9 Wtx mTOR1 Y1163 Y1101 Gab1 Apc PI3K Y727 Y1167 PI3K Y759 RASGAP Y1168 MAPK Rac GTP Y1148 SHC GRB2 p120 p120 Y815 SHIP2 RhoGEF RalGEF p70-S6K Y1215 ! ! Y1175 SOS GTP Y891 phos SHP1 Cdc42 Y903 SHIP2 Y1253 SHP2 GRB2 ! ! PTP1 MKK1/2 PI3K Y935 Wtx GTP CT ! Rho PI3K Y983 SHIP2 Y1282 GRB2 SHP2 Y1006 Y1283 RalBP1 RalA/B GTP MP1 axin PI3K Y1352 PI3K Erk1/2 GSK3 Sprouty Apc MKP1 GTP GRB2 SHP2 Y1173 Rac 1. Lamellopedia# GRB2 SHP2 Y1220 Cdc42 GTP 2. Filopedia;+-9 MMP 3. Degrade ECM RSK1 ETS CREB FOXO 1. Block Apoptosis Erk1/2 1. Block Apoptosis ORGANELLES: KEY SMALL MOLECULES: 2. Unblock Cell-cycle T58 S62 2. Drive Cell-cycle FOS MYC ELK1 3. Translation(growth) 3. Transcription GTP ; mTOR1 4. Monitor Nutrient + O SAP1 MACROMOLECULES: 2 ! cJun p53 4. Monitor DNA GDP 5. Glycolysis + FA synth 5. Gln + Warburg + DNA GTP Guanine-Exchange Factor (GEF) GLUT1 HK2 ACLY ASCT2 LDH PRPS2 G-Proteins GTPase-Activating Protein(GAP) cGMP cAMP Calcium sugar AP-1 pro-survival T58 S62 cyclin-D1 Endoplasmic Mitochondria pro-apoptosis NETWORK: TCF/LEF MYC Reticulum !CBP poly-Actin Cell-cycle Checkpoint Generic Activation Generic Inhibition Transcription Elongation Proliferative Re-wiring sensor Biosynthetic Enzyme Max RNApol2 Activating Phosphorylation MYC E-Box Deactivating Phosphorylation express-gene CKS1 CDK4 NNNN Transcription-Factor Binding Ubiquitination SKP2 DNA Cul1 Ac- Acetylation Lysosome Autophagosome RNA Spliced-RNA t-RNA Me- Methylation METABOLISM TRANSLATION CELL CYCLE PERMIT Growth Factor Control #1 Growth Factors Enable SLOW PI3K/AKT RAS/ERK APPROVED STOP OP OPOPO:9#P PI3K/AKT RAS/ERK ! RAS/ERK mTOR PI3K/AKT AS160 GLUT1 O;9 O O6!P O*=$P T58 S62 #2 Check MYC Pentose Pathway T58 S62 MYC 8P P TSC2 Glucose ATP AMP ATP ATP ATP ATP ATP RHEB GLUT1 6PGC Ru5P AMP RSK1 T58 S62 Raptor TSC1 R5P PPAT IMP ADSL PRPP AICAR-T GAR-T AIR-S AIR-C IMP-S Building FGAM-S GAR-S ADS-S ADS-L SAICAR-S PGD NADH RPIA GTP mTOR1 PRPS2 RDS D HK2 QE G fTHF THF QE CO2 D fum fTHF THF IMPDH fum RDS PGLS Q MYC RDS ATP ATP 2ATP 2ATP GMP-S E - HCO3 S6K PS-II HOase TCase Materials DHO Orotate UMP UTP CTP Smad2/3 CPT-S UMP-S DHOD A D NMPKs NDPKs GS G6P 6PGL C mTHF GMP QED OH- CoQ CoQH QE Arg Smad4 2 CO2 TYMS ! G6PD2 THF RSK1 & p53 CAGAC p130/107 p53 1/2 PGI p70-S6K TTP TSC2 9 (12h) FOXO4 E2FDP (glycosylation) G1 4/5 1/2 CAT AMPK ! F2,6P F6P GFPT1 poly- cyclinD PFKFB2 SAM amines TSC1 MAT MeTs Pro INK4 RB RB proteins S62 T58 PFK1 p15 AP-1 ! SAH ODC PYCR1 MYC Met formate p16, p27 b12 18,19 F1,6P AHCY Arg urea E2FDP Gln onco-rewiring MTR Arg1 negative ASL Asn feedback Asp 1-3 1/2 fTHF AA’s TTTCCCGC meTHF SN2 MTHFD R-suc Orn NH4 lysosome DHAP ALDO NOS CO2 ' C /6 ASNS ASCT2 RHEB clin D + CDK4 Ragulator 2 MTHFR GLS2, nutrients OTC dUMP dTMP NO ASS Gln RAGA/B STAT3 K PRPS2 New Raptor GO ARF G3P Cit RAG RAGC/D D Gly mTHF TYMS Glu GTPases C Cdc25A Asp EAA GAPH + mTOR1 G0 E LAT1 SHMT b6 DHF DHFR c 21415167 p21 1,3BPG STOP C Ser THF DHFR L,I,V;* K,M M(1h) ATP PGK PSP folate STOP folate #3 Ribosome PP2A RPRM C MDM2 AA Metabolism p70-S6K P-Ser FolR 4EBP c (6h) GADD45 B S PIP PG CL Assembly MAF1 + *88 PSAT x &'(( C D CDIPT PGS1 CRLS1 eIF4G K 2 p53 3PG 3PHP 1 K GPD1 BN51 *& D PHGDH SPM eIF4B eIF4A +C CDP-DAG eIF4E Cdc25B/C Wee1 cA PGM glycerol SKAR RNApol-III C SPTLC 3-phosphate CDS acetate mRNA p53 2PG FASN FFA-CoA GPAT PA DAG DGAT TAG p38 MK2 (4h) s6 r,t,miRNA ((Pu)3-CATG-(Py)3-(x)0-13)2 Mal-CoA PCYT1 PCYT2 eEF2K G2 Cdc25A ENO sterols CHK1 ACC PTDSS1 40SRibo RDS PC PS PE Glycolysis PEP HMGCR AcCoA eEF2 Nucleolin SREBP1 Akt Fat Biosynthesis ACSS2 .: PKM2 ACLY .: CHK2 GDP GTP ATP lysosome LDL START citrate Claspin MRE11 Nbs1 Ac-CoA CS ACO TopBP1 MRE11 Nbs1 eIF2B ATR RAD50 LDLR TOPBP1 BACH1 Ac- RAD50 MRN complex Ala eIF4G ATRIP ATM Asp MDC1 MRE11 Nbs1 MDC1 OAA isoc RPA eIF4E eIF4B eIF4A PCNA Ac- RAD50 LDH PDH IDH CtIP -Ac 53BP1 Gln #4 Translation Pol-$ MDH mRNA Lac GLS ICL p21 H2AX MCT PDK malate TCA !" GDH Glu Gln mRNA H2AX GS BRCA1 PALB2 SN2 s6 Ribo 9-1-1 FUM Cycle ASCT2 -some BRCA2 fumarate suc-CoA 80SRibo Fork Collapse dsDNA Breaks RAD51 amino Homologous Non-Homologous SDH SCS protein ERAD acids succinate proteo Recombination End Joining T58 S62 -some MYC O2 Cell-Cycle Checkpoint Control ##;<6 UNFOLDED PROTEIN AUTOPHAGY RESPONSE APOPTOSIS #2 Autophagosome Initiation #3 Autophagosome Formation O&'*+P O#.0*+P - 0*1*3 BiP Autophagy Autophagy ATF6f STOP Energy GO STOP Energy GO Growth Signals Stress Signals DNA damage & #+112 UNFOLDED TRAF2/6 ROS RAS/ERK PI3K/AKT TAK1 PPROTEIN TAB1 TAB2 Trx[R] AMP Amino-Acids NAD+ tRNA RSK1 MEKK1/4 p53 MLK1/2/3 (p63/73) RAG IRE1 STOP ASK1/2 AMPK GTPases SIRT1 GCN2 p300 IRE1 IRE1 PERK XBP1u mRNA NORMAL TRANSLATION MKK7 MKK4 MKK3/6 XBP1s RHEB FOXO1/3 #1 Growth/Stress TSC2 TSC1 ATF4 mRNA enable Autophagy mTOR1 Ribo JNK -some p38 BAD BIM NOXA Erk1/2 JNK ATG12 Immune Cell LC3 amino PUMA ATG7(E1) ERAD ATG4 eIF2B’ ATG10(E2) BiP protein acids ERAD proteo Vac8 FIP200 -some ULK LC3 GDP ATG13 ATG17 !"#$ Bcl-2 ATG11 ATG7(E1) cytoskeleton ATG12 ATG12 STOP Bcl-2 ATG5 ATG5 ATG3(E2) breakdown PtdIns PI3P ATG3(E2) BMF ATG16 ATG16 LC3 ATG14L VSP34 VSP15 PE Beclin1 GO Bcl-xl Beclin1 PIK3R4 BIK Ambra UVRAG LC3-II REPAIR TRANSLATION Death Bif-1 Ligands Bax, # TRADD tBID RIP Rubicon ATF4 FADD DISC Bak # proCasp ROS, AIF, TRAF2/6 auto-activate MyD88/ endonuc-G then # Beclin1 Casp-2/8 Autopha- auto-deactivate Smac/DIABLO CytC gosome # Casp-10 Omi/HtrA2, ARTS, Apaf1 REPAIR Casp-12 XAF1 Apaf1 Calpain IRE1 IRE1 IRE1 IRE1 proCasp-9 ER Stress TRAF2/6 IAP TAB1 TAB2 ATF6f TAK1 Casp-9/3/6/7 Lysosome CHOP BIM TRAF2 TRAF2 TRAF2 TRAF2 STAT3 Casp9 ATF4 ' Ca2+ Casp-8 Survival FADD PARP Calpain actin, proCasp vimentin, Lysosome Casp-9/3/6/7 plectin, 400-1000 targets gelsolin ER Stress JNK/p38 H2O2 PS DEATH PS PS APP Rock CAD APOPTOSIS lamin/ICAD #4 Insufficient Lysosome Activity/Autophagosome Turnover can lead to Cell Death 15 21 P ractically Sc ience.com.