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Direct Stimulatory Modification Direct Inhibitory Modification Multistep Stimulatory Modification Multistep Inhibitory Modification Tentative Stimulatory Modification Tentative Inhibitory Modification Kinase Phosphatase Transcription Factor Caspase Receptor Enzyme pro-apoptotic pro-survival GAP/GEF GTPase G-protein Acetylase Deacetylase Ribosomal subunit Separation of Subunits or Cleavage Products Joining of Subunits Translocation Transcriptional Stimulatory Modification Transcriptional Inhibitory Modification 48S 43S 40S 60S 40S 60S 40S 60S eIF5B eIF5B eIF6 DHX29 eIF3 eIF1 eIF1A eIF2 PABP eIF4F eIF2 Met-tRNAi eIF1A eIF1 eIF3 eRF1 eRF3 eEF1 eEF2 eEF2K eIF4B 40S 60S 48S eIF4 Control: Growth Factors (mTORC1), Hormones, Cytokines, Mitogens, Neuropeptides, Oxidative Stress eEF2 Control: Ca 2+ cAMP mTORC1 Initiation Stress Granules P-bodies ON eIF2 Control: Viral Infection (dsRNA), (PKR) Amino Acid Starvation, UV Light (GCN2) Heme Deficiency (HRI) Heat Shock, ER Stress, Hypoxia (PERK) OFF miRNA miRNA Elongation Nascent Polypeptide A (n) Cap AUG Cap Polypeptide Chain Factor Release Scanning Initiation Codon Recognition ER Lumen Termination A(n) AUG A (n) Cap AUG A (n) AUG GTP GTP GDP GDP GTP GTP GTP A (n) Cap Cap AUG AAAAA Cap Initiation Complex eIF5 eIF5 Translational Control: Overview © 2002–2015 Cell Signaling Technology, Inc. GADD34 NCK BiP PP1 GCN2 eIF2 Met-tRNAi Ternary Complex α β α β eIF2 γ eIF2 γ eIF2 γ eIF2 γ α β α β eIF2B eIF2B eIF5 eIF5 eIF5 eIF5 PP1 PTEN CreP SirT1 SirT1 HRI PKR PKR PERK PERK GCN2 HRI GSK-3β eIF2B Akt eIF1 eIF1A eIF3 40S 43S Growth Factors, Hormones, etc. Salubrinal Global Translation Off ATF-4, CHOP, mRNA Translation Apoptosis, Changes in Metabolism & Redox Status Global Translation On Growth Factors, ER Stress, Viral Infection dsRNA Unfolded Protein Response, Hypoxia Glucose Deprivation, UV Light, Amino Acid Starvation Heme Deficiency, Oxidative Stress GDP GDP GDP GDP GTP GTP GTP Met-tRNAi Translational Control: Regulation of elF2 © 2003–2015 Cell Signaling Technology, Inc. p38 MAPK Erk PRAS40 p70 S6K TSC1 TSC2 eIF4B eIF4H MNK 4E- BP1 4E- BP1 eIF4G eIF4E eIF4E PTEN PDK1 PI3K IRS-1 LKB1 AMPK PABP PABP Akt S6 p90RSK eIF4F eIF4F eEF2K PAIP1 PAIP2 Hormones, Growth Factors, Cytokines, Neuropeptides Mitogens Stress elF4A PDCD4 Wnt Frizzled LRP Gα q/o Dvl GRB10 RagA/B RagC/D GSK-3 FKBP12 TBC1D7 mTORC2 mTORC1 43S 48S Translation Off Translation Elongation On Translation On rapamycin Torin1 PP242 KU63794 WYE354 Amino Acids PIP 3 Cap AAAAA AMP: ATP mTORC2 mTOR Rictor Sin1 PRR5 DEPTOR Raptor GβL mTOR DEPTOR mTORC1 GβL eEF2 Translational Control: Regulation of elF4E and p70 S6K © 2002–2015 Cell Signaling Technology, Inc. Transcriptionally Inactive Chromatin Transcriptionally Active Chromatin SUV 39h Me HP1 SUV 39h Me HP1 SUV 39h Me HP1 SUV 39h Me HP1 Me PC PRC1 Me PC PRC1 Me PC PRC1 Me PC PRC1 Me BPTF NURF Me BPTF NURF Me Me Me Me Me Me Me Me Me Me Me Me Me Me Pericentric Heterochromatin Inactive X Chromosome Rb-Mediated Repression Pericentric Heterochromatin Inactive X Chromosome Hox Gene Repression Anti-Silencing Transcription Initiation Transcription Elongation Methylation H3K9me Demethylation Methylation Demethylation Methylation H4K20me Demethylation Methylation H3K27me Demethylation Methylation H3K79me Demethylation Methylation H3K4me Demethylation H3K36me H3K4me Methylases: MLL1/KMT2A (+,†,‡) MLL2/KMT2B (+,†,‡) MLL3/KMT2C (+) MLL4/KMT2D (+) SET1A/KMT2F (+,†,‡) SET1B/KMT2G (+,†,‡) NSD3/KMT3F (+,†) NSD2/KMT3G (+,†) SET7/KMT7 (†) SMYD3/KMT3E (†,‡) ASH1L/KMT2H (+,†,‡) PRDM9/KMT8B (‡) Demethylases: LSD1/KDM1A (+,†) AOF1/KDM1B (+,†) JARID1A/KDM5A (†,‡) JARID1B/KDM5B (†,‡) JARID1C/KDM5C (†,‡) JARID1D/KDM5D (†,‡) Methylation Degree: + Mono † Di ‡ Tri H4K20me Methylases: SET8/KMT5A (+) NSD1/KMT3B (+,†) ASH1L/KMT2H (+,†,‡) SUV420H1/KMT5B (†,‡) SUV420H2/KMT5C (†,‡) NSD2/KMT3G (+,†) Demethylases: JHDM1D/KDM7A (+,†) PHF8/KDM7B (+,†) H3K9me Methylases: PRDM3/KMT8E (+) PPRDM16/KMT8F (+) G9a/EHMT2 / KMT1C (+,†) EHMT1/KMT1D (+,†) ASH1L/KMT2H (+,†,‡) PRDM2/KMT8A (+,†,‡) PRDM8/KMT8D (†) SUV39H1/KMT1A (†,‡) SUV39H2/ KMT1B (†,‡) ESET/KMT1E (†,‡) CLLD8/KMT1F (†,‡) Demethylases: AOF1/KDM1B (+,†) JMJD1A/KDM3A (+,†) JMJD1B/KDM3B (+,†) JMJD1C/KDM3C (+,†) JHDM1D/KDM7A (+,†) PHF8/KDM7B (+,†) JMJD2A/KDM4B (†,‡) JMJD2B/KDM4B (†,‡) JMJD2C/KDM4C (†,‡) JMJD2D/KDM4D (†,‡) KDM4E/KDM4DL (†,‡) H3K27me Methylases: Ezh2/KMT6 (+,†,‡) NSD2/KMT3G (+,†,‡) NSD3/KMT3F (†,‡) Demethylases: JHDM1D/KDM7A (+,†) PHF8/KDM7B (+,†) UTX/KDM6A (†,‡) JMJD3/KDM6B (†,‡) H3K36me Methylases: NSD1/KMT3B (+,†) SMYD2/KMT3C (+,†) NSD2/KMT3G (+,†) SET2/KMT3A (‡) Demethylases: JMJD1A/KDM2A (+,†) JMJD1B/KDM2B (+,†) JMJD2A/KDM4A (†,‡) JMJD2B/KDM4B (†,‡) JMJD2C/KDM4C (†,‡) JMJD2D/KDM4D (†,‡) KDM4DL/KDM4E (†,‡) H3K79me Methylases: DOTIL/KMT4 (+,†,‡) Demethylases: ??? Histone Lysine Methylation © 2002–2015 Cell Signaling Technology, Inc. NcoR Su Su HDAC NuRD Sin3 TF TFIIA p53 TBP TFIID TFIIH RNA Pol II TFIIE TFIIF TFIIB CBP/ p300 PCAF SRC-3 TF TATA TF CBP/ p300 PCAF SRC-3 Tip60 Tip60 Tip60 Rb GCN5L2 ATM Sirtuins SirT1 SirT1 SirT3 BRCA1 AceCS1 AceCS1 PEPCK PEPCK PGC-1α Idh2 PGC-1α Idh2 α-Importin Regulatory Signaling Pathways Signaling Pathways Fatty Acid Synthesis Histone Acetylation Gluconeogenesis Expression of Gluconeogenic Genes NADPH Cell Cycle Protein Acetylation Histone Acetylation Cytoskeletal Regulation Ribosomal Proteins Chaperones RNA Splicing Deacetylation BMP, Wnt, Notch Transcription Pluripotency Development Differentiation of Neural Stem Cells ATF-2 CBP CDY CLOCK EWI Elp3 GCN5L2 GRIP HAT1 HBO1 MCM3AP Acetyl Transferases Acetylation Nuclear Transport Histones Stability Stability DNA Damage DNA Damage Metabolism DNA Repair HDAC Classes Class I: HDAC1-3, 8 Class II: HDAC4-7, 9, 10 Class III: SIRT1-7 Class IV: HDAC11 MORF MOZ p300 PCAF p/CIP SRC-1 SRC-3 hTAF II 250 TFIIB Tip60 Deacetylases Acetylases Protein Acetylation © 2002–2015 Cell Signaling Technology, Inc. Su p53 p53 p53 CBP/ p300 TIP60 MOF Ub Ub Ub Ub Calcineurin MEF2A MDM2 14-3-3 H3 H3 H3 Pim-1 P-TEFb MDM2 HP1 HP1 BRD4 HP1 GCN5 HATs Chk2 Set7/9 MEF2A Histone H3 Histone H3 and H4 p53 MEF2A Resting Neurons dissociation dissociation Transcription Aurora B, Ras K372 S20 S20 K120 K372 K381 K382 K372 K373 K381 K382 DNA Damage p53 Ubiquitination/Degradation Transcriptional Repression Transcriptional Activation p53 Stability/Transactivation of pro-apoptotic target genes Membrane Depolarization Ca +2 S408 S408 Dendric Claw Differentiation No Differentiation Transcriptional Repression Transcriptional Activation K403 K403 K9 K9 K9 K14 K14 K14 S10 S10 S10 K16 Me Me H3 S10 H4 Me PIAS1 RNA Pol II Examples of Crosstalk Between Post-Translational Modifications © 2003–2015 Cell Signaling Technology, Inc.