CST Signaling Pathway Diagrams for & Translational Control

Protein Acetylation Translational Control: Overview © 2002–2015 Cell Signaling Technology, Inc. © 2002–2015 Cell Signaling Technology, Inc. eIF4 Control: Histone Regulatory Acetylation eIF2 Control: Acetyl Growth Factors (mTORC1), Acetylation Signaling Pathways Viral Infection (dsRNA), Transferases Hormones, Cytokines, Mitogens, (PKR) DNA ATF-2 MORF Neuropeptides, Oxidative Stress Amino Acid Starvation, Damage CBP MOZ ON UV Light (GCN2) eEF2 Control: CDY p300 Heme Deficiency (HRI) Ca2+ PCAF Tip60 PCAF CLOCK PCAF Heat Shock, ER Stress, CBP/ CBP/ cAMP p300 Su p300 Su EWI p/CIP DHX29 Hypoxia (PERK) Elp3 SRC-1 mTORC1 Initiation Codon SRC-3 SRC-3 GCN5L2 SRC-3 Recognition GRIP hTAF 250 II Scanning 48S HAT1 TFIIB 48S α-Importin Cap OFF BRCA1 HBO1 Tip60 AUG miRNA A MCM3AP Factor Cap (n) AUG Nuclear Transport Transcription Release TFIIH Pluripotency eIF1 A(n) Initiation TFIID Development Initiation Complex TFIIF eEF2K eIF4B TFIIA TBP RNA Pol II Differentiation of TF TF TFIIB Neural Stem Cells eIF5 43S TATA TFIIE TF BMP, Wnt, Notch eIF4F eIF2 Cap GDP Stress Granules AUG P-bodies PABPA Histones Deacetylation (n) eIF3 eIF2 eIF6 Met-tRNAi GTP miRNA Sirtuins eIF1A HDAC 40S HDAC Classes NuRD Cap AUG A Class I: HDAC1-3, 8 NcoR (n) eIF5B Sin3 Class II: HDAC4-7, 9, 10 60S GTP Class III: SIRT1-7 60S eIF1 eIF1A Class IV: HDAC11 Signaling Pathways GTP eIF5B eEF1 eIF5 GDP GCN5L2 Elongation Acetylation Tip60 SirT1 Fatty Acid Synthesis AceCS1 AceCS1 eEF2 Histone Acetylation GTP eIF3 Tip60 Rb ATM PEPCK PEPCK Gluconeogenesis 40S A(n) SirT1 AUG α α Cap Cap Stability DNA Stability PGC-1 PGC-1 Expression of 60S 40S Repair Gluconeogenic SirT3 60S 40S Idh2 Idh2 NADPH AAAAA Nascent DNA Damage Metabolism Polypeptide Polypeptide Chain Termination ER Lumen

Acetylases Deacetylases

eRF1 Cell Cycle RNA Splicing eRF3 Cytoskeletal Regulation Chaperones Ribosomal GTP

Histone Lysine Methylation Translational Control: Regulation of elF2 © 2002–2015 Cell Signaling Technology, Inc. © 2003–2015 Cell Signaling Technology, Inc.

Unfolded Protein Transcriptionally Inactive Transcriptionally Active Akt Response, Hypoxia Chromatin Glucose Deprivation, UV Light, Amino Acid NURF Growth Factors, NURF BPTF Starvation Me PTEN ER Stress, Me BPTF Me BiP Me Viral Infection Heme Deficiency, Me Me dsRNA Oxidative Stress Salubrinal Me PERK GCN2 Me Methylation PERK GCN2 Pericentric Heterochromatin DemethylationH4K20me PKR HRI PKR Methylation HRI SUV SUV SUV SUV 39h 39h 39h 39h H3K4me Transcription Initiation HP1 HP1 HP1 HP1 Demethylation Growth Factors, Me Me Me Me Hormones, etc. PP1 Methylation Methylation Me SirT1 Me Me α β H3K9me H3K36me Me GADD34 Demethylation Demethylation PP1 eIF2 γ Pericentric Heterochromatin CreP SirT1 GDP eIF5 Inactive X Rb-Mediated Repression Methylation α β H3K79me β Demethylation Transcription Elongation GSK-3 γ Methylation eIF2 PRC1 PRC1 PRC1 PRC1 PC PC PC PC NCK Me Me Me Me GDP H3K27me eIF2B eIF5 Demethylation GTP Me Me

Me Me GDP eIF2B α β Inactive X Chromosome Hox Repression Anti-Silencing eIF2 γ eIF2B GTP Methylation Degree: + Mono † Di ‡ Tri α β Met-tRNAi H4K20me H3K9me H3K27me H3K4me H3K36me H3K79me Methylases: Methylases: Methylases: Methylases: Methylases: Methylases: eIF2 γ SET8/KMT5A (+) PRDM3/KMT8E (+) Ezh2/KMT6 (+,†,‡) MLL1/KMT2A (+,†,‡) NSD1/KMT3B (+,†) DOTIL/KMT4 (+,†,‡) GTP NSD1/KMT3B (+,†) PPRDM16/KMT8F (+) NSD2/KMT3G (+,†,‡) MLL2/KMT2B (+,†,‡) SMYD2/KMT3C (+,†) : GDP eIF5 eIF2 ASH1L/KMT2H (+,†,‡) G9a/EHMT2/KMT1C (+,†) NSD3/KMT3F (†,‡) MLL3/KMT2C (+) NSD2/KMT3G (+,†) ??? Met-tRNAi SUV420H1/KMT5B (†,‡) EHMT1/KMT1D (+,†) Demethylases: MLL4/KMT2D (+) SET2/KMT3A (‡) Ternary SUV420H2/KMT5C (†,‡) ASH1L/KMT2H (+,†,‡) JHDM1D/KDM7A (+,†) SET1A/KMT2F (+,†,‡) Demethylases: 40S Complex NSD2/KMT3G (+,†) PRDM2/KMT8A (+,†,‡) PHF8/KDM7B (+,†) SET1B/KMT2G (+,†,‡) JMJD1A/KDM2A (+,†) Demethylases: PRDM8/KMT8D (†) UTX/KDM6A (†,‡) NSD3/KMT3F (+,†) JMJD1B/KDM2B (+,†) ATF-4, CHOP, mRNA JHDM1D/KDM7A (+,†) SUV39H1/KMT1A (†,‡) JMJD3/KDM6B (†,‡) NSD2/KMT3G (+,†) JMJD2A/KDM4A (†,‡) Translation eIF3 PHF8/KDM7B (+,†) SUV39H2/KMT1B (†,‡) SET7/KMT7 (†) JMJD2B/KDM4B (†,‡) eIF1 ESET/KMT1E (†,‡) SMYD3/KMT3E (†,‡) JMJD2C/KDM4C (†,‡) CLLD8/KMT1F (†,‡) ASH1L/KMT2H (+,†,‡) JMJD2D/KDM4D (†,‡) Demethylases: PRDM9/KMT8B (‡) KDM4DL/KDM4E (†,‡) eIF5 eIF1A AOF1/KDM1B (+,†) Demethylases: JMJD1A/KDM3A (+,†) LSD1/KDM1A (+,†) JMJD1B/KDM3B (+,†) AOF1/KDM1B (+,†) JMJD1C/KDM3C (+,†) JARID1A/KDM5A (†,‡) 43S JHDM1D/KDM7A (+,†) JARID1B/KDM5B (†,‡) Apoptosis, Changes in PHF8/KDM7B (+,†) JARID1C/KDM5C (†,‡) Metabolism & Redox Status JMJD2A/KDM4B (†,‡) JARID1D/KDM5D (†,‡) JMJD2B/KDM4B (†,‡) JMJD2C/KDM4C (†,‡) Global Translation Off Global Translation On JMJD2D/KDM4D (†,‡) KDM4E/KDM4DL (†,‡)

Examples of Crosstalk Between Post-Translational Modifications Translational Control: Regulation of elF4E and p70 S6K © 2003–2015 Cell Signaling Technology, Inc. © 2002–2015 Cell Signaling Technology, Inc.

Hormones, Growth Factors, Histone H3 Aurora B, Ras GCN5 HP1 Cytokines, Neuropeptides Wnt Mitogens Stress S10 K14 Amino Acids HP1 K9 Frizzled S10 H3 LRP Me K14 Transcriptional K9 Transcriptional Repression H3 HATs Activation PTEN α PIP3 G q/o S10 PI3K Dvl K14 IRS-1 K9 H3 dissociation HP1 PDK1 mTORC2

Histone H3 and H4

LKB1 Akt Pim-1 Erk p38 MAPK AMP: AMPK GSK-3 MOF P-TEFb ATP TSC2 BRD4 14-3-3 GRB10 S10 K16 TSC1 TBC1D7 Transcription H3 H4 RNA Pol II RagA/B PRAS40 rapamycin RagC/D FKBP12 p90RSK p53 DNA Damage Torin1 mTORC1 PP242 KU63794 Chk2 Set7/9 WYE354 MDM2 TIP60 K120 Ub K372 K372 dissociation Me S20 Me K372 p70 S6K MDM2 Ub K373 S20 CBP/ p53 p53 p53 K381 Ub K381 p300 Ub K382 S6 PDCD4 eIF4B K382 eEF2K eEF2 p53 Ubiquitination/Degradation p53 Stability/Transactivation of pro-apoptotic target genes Translation Elongation On elF4A eIF4H MEF2A Ca+2 MNK Resting Neurons Membrane Depolarization 4E- eIF4E eIF4G BP1 eIF4E PABP PIAS1 Calcineurin eIF4F PAIP1 K403 Su S408 K403 S408 Translation Off 4E- PAIP2 BP1 MEF2A MEF2A 43S mTORC1 mTORC2

PRR5 eIF4F 48S Dendric Claw GβL Raptor Sin1 Cap mTOR Rictor GβL Differentiation No Differentiation DEPTOR Translation On mTOR Transcriptional Repression Transcriptional Activation DEPTOR PABP AAAAA

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

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