CST Signaling Pathway Diagrams for; Cell Growth and Death

Regulation of Overview Inhibition of Apoptosis © 2002–2015 Cell Signaling Technology, Inc. © 2002–2015 Cell Signaling Technology, Inc. α TNF- Survival Factors: TNF, FasL, TRAIL Growth Factors, TNF, FasL, TRAIL Trophic Factors Cytokines, etc. TNF-R1

cIAP CYLD PTEN A20 Cytoplasm TRAF2 RIP1 TRADD

Ras c-IAP

RIP PI3K

Itch FADD TRADD FADD

TRAF2 Raf

RIP1

TRADD TRAF2 c-IAP NIK TAK1 FLIP Cytoplasm CYLD ASK1 PKC HSP90 FLIP RIP RAIDD PI3K TAB TAK1 Casp-8 JNK PIDD PIP3 PDK1 Cell Cycle FADD TRADD Casp-2 p90RSK Erk1/2 IKKγ CDC37 IKKα IKKβ FADD Bax IKKβ HSP90 IKKγ α β Casp-8,-10 p53 IKK IKK NIK JNK Bcl-2 Bad cdc2 BID GSK-3 Akt p70S6K Erk1/2 PKC Jak Src IKKγ RIP Bak SirT2 Bcl-xL HSP90 TRAF2 Bax FoxO1 BID 14-3-3 Akt Smac/ Bim Noxa κ Bak Bcl-2 I B Diablo Bax HtrA2 Casp-12 tBID Puma NF-κB tBID Bcl-xL Bad p90RSK Cellular Stress XIAP Arts Bim IκBα FoxO1 Bim Mcl-1 HECTH9 IκB Casp-3,-6,-7 Bax Smac/ Mcl-1 PKA FoxO1 CREB Stat1 Stat3 NF-κB Calpain Casp-9 XIAP Diablo HSP27 NF-κB Apoptosis Cyto c AIF Endo G Casp-9 JNK [cAMP] IκBα Apaf-1 Cyto c HECTH9 HSP70 Bim Akt NF-κB [Ca2+] Casp-3,-6,-7 Casp-9 HSP90 HSP70 HSP27 PARP Apaf-1 Chk1/2 DFF45 Cytoplasm ROCK Lamin A/C ATM/ATR p53 Nucleus DFF40 FLIP CREB XIAP FAS Bcl-2 ER Stress Bim Bcl-xL Stat1 APP NF-κB A20 FoxO1 Stat3 • Cell shrinking • Membrane blebbing Cytoplasm Death Receptor Signaling p53 © 2002–2015 Cell Signaling Technology, Inc. Nucleus DFF40 AIF Endo G α FoxO1 JNK TNF-α TNF- APO-3L/ TWEAK FLIP Puma APO-2L/ Bim FasL XIAP Noxa TRAIL TNF-R1 TNF-R2 DR3 DNA NF-κB Fas/ APO-3 p53 c-Jun CD95 Fragmentation DNA Damage TRADD DR4/5 FADD TRAF2 RIP1 TRAF2 TRAF1 RIP Daxx cIAP1/2 CYLD cIAP1/2 TRADD TRADD IKKα/β/γ ASK1 Casp-8, -10 FADD RIP TRAF3 FADD ub Casp-8,-10 BID FLIP Mitochondrial Control of Apoptosis TRAF2 TRAF1 IκB cIAP1/2 © 2003–2015 Cell Signaling Technology, Inc. tBID Complex Complex NF-κB IIb Death Stimuli: MKK1 IIa FasL Cyto c Survival Factor Withdrawal NIK Survival Factors: Casp-8 Casp-8 Bcl-2 RIP1 Growth Factors, Cytokines, etc. JNR FADD RIP3 FADD RIP1 Fas/ IKKα Bcl-2 CD95 MLKL

Apaf1 NF-κB Casp-9 Smac IκB RelB FADD Bim p100 LC8 Active Casp-8,-10 XIAP XIAP Caspase-8

Microtubules Processing DLC2 PI3K HECTH9 Casp-6 Bmf JNK Necroptosis Casp-3 Casp-7 Erk1/2 BID Mcl-1 JNK p65/ NF-κB Hrk PKC Bcl-xL Bim RelA p50 Bcl-2 tBID ARD1 Lamin A Actin GAS2 α-Fodrin ROCK1 DFF45 Acinus PARP p52 RelB Bmf NatA PKA p90RSK Akt p70 S6K Hrk Bax Acetyl-CoA DFF40 Bcl-2 Cell Shrinkage DNA Chromatin Transcription tBID Membrane Blebbing Fragmentation Condensation CaMKII Calcineurin Bax Apoptosis Survival Bad Bax Bak 14-3-3 Bak Bcl-2 Casp-2 RAIDD Cell Cycle Control: G1/S Checkpoint Noxa Bad © 2002–2015 Cell Signaling Technology, Inc. PIDD 14-3-3 [NAD] Growth Factor Bcl-xL Bcl-2 Receptor Activation Akt Bad Mcl-1 Puma Apaf-1 TGF-β DNA SirT2 Replicative Damage Cytosolic Cyto c Senescence Sequestration Casp-9 FoxO1/3

p53 Differentiation ATM/ Arts HECTH9 ATR HSP60 HtrA2 Hormones Smad3 BMI1 Myc Smac/ Endo G Smad4 p53 XIAP Diablo ATM/ Ultra Violet Replicative AIF ATR ING2 Senescence Casp-3 ub Stress Response

p21 Cip1 Chk1/2 p19 INK4D p18 INK4C p16 INK4A p15 INK4B DNA Damage Genotoxic Stress Myc Growth p27 Kip1 Ubiquitination Factor Apoptosis Withdrawal Myc Myc cdc25A GSK-3β Signaling SCF © 2003–2015 Cell Signaling Technology, Inc. SCF CDK4/6 Macroautophagy CDK2 Mitophagy PI3K-I/Akt MAPK/Erk1/2 Ubiquitination Cyclin D Cyclin E Ubiquitination Mitochondrial ub R Signaling Signaling E S Damage Parkin HAS -PH 1-P ASE AMP: G AMPK p53/Genotoxic ATP PINK Stress ub -targets Suv39H1 PARL Abl HDAC Rb E2F/DP Target : Amino Rb Cyclin E/A, E2F-1/2/3, FoxO1 Bim Acids E2F E2F cdc2, c-Myc, p107, BNIP3 FasL β mTOR Raptor DBE Apoptosis DP-1 DP-1 RanGAP, TK, DHFR, G L TRAIL OFF ON PCNA, H2A, etc. PRAS40 BNIP3L/NIX

Atg13 FIP200 Cell Cycle Control: G2/M DNA Damage Checkpoint Oxidative ULK1 Stress © 2002–2015 Cell Signaling Technology, Inc. IR UV p150 Critically Short FANCD2 PI3K SQSTM1/p62 Telomeres Class III POT1 TRF2 DNA NBR1 Repair Beclin-1 Membrane LC3-II Rad50 + DNA Repair NBS1 Bcl-2 Atg14 Nucleation Mre11 Ambra1 ATM/ (MRN) Ambra1 ATR HIPK2 DNA-PK Apoptosis Rubicon Caffeine BRCA1

BRCA1 Sequestration WIP1 c-Abl Rad51 Phagophore MDM4 Nuclear Export, Ubiquitination p53 Chk2 Rad52 Autophagosome Chk1

Nucleolar SQSTM1/p62 Arf 14-3-3 Sequestration p19 cdc25A ub or MDM2 ub p53 Stabilization Atg16L1 Atg12 Atg5 NBR1 LC3-II TRIP12 p300/ cdc25A/C Nuclear Exclusion + + p53 PCAF cdc25 Ubiquitination Cytoplasmic cdc25A/B ALFY Contents WIP1 AurA Bora PLK1 TopoII BRCA1 14-3-3σ Reprimo GADD45 p21Cip1 CDK7 SCF Atg16L1 Fusion p90RSK Atg3 PE Myt1 Atg5 Nuclear Atg10 Atg7 Exclusion SCF Autophagolysosome Atg7 LC3-I Wee1 Ubiquitination Lysosome cdc2 M Atg12 ASE Cyclin B -PH Atg4 -PH AS G2 E LC3

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

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