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CST Signaling PaThway DiagramS for

Epigenetics & Translational Control

www.cellsignal.com/genepws14PSTREFMGENE0265ENG_00

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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 40S60S

eIF5B

eIF5B

eIF6

DHX29

eIF3

eIF1

eIF1A

eIF2PABP

eIF4F

eIF2Met-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:Ca2+

cAMPmTORC1

Initiation

Stress GranulesP-bodies

ON

eIF2 Control: Viral Infection (dsRNA),(PKR) Amino Acid Starvation, UV Light (GCN2)Heme Deficiency (HRI)Heat Shock, ER Stress, Hypoxia (PERK)

OFFmiRNA

miRNA

Elongation

NascentPolypeptide

A(n)Cap

AUGCap

PolypeptideChain

FactorRelease

Scanning

Initiation CodonRecognition

ER LumenTermination

A(n)

AUGA(n)Cap AUG

A(n)

AUG

GTP

GTP

GDP

GDP

GTP

GTP

GTP

A(n)

Cap

Cap

AUG

AAAAA

Cap

InitiationComplex

eIF5

eIF5

Translational Control: Overview© 2002–2015 Cell Signaling Technology, Inc.

GADD34

NCK

BiP

PP1

GCN2

eIF2Met-tRNAiTernary 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

HRIPKRPKR

PERKPERK

GCN2

HRI

GSK-3β

eIF2B

Akt

eIF1

eIF1A

eIF3

40S

43S

Growth Factors,Hormones, etc.

Salubrinal

Global Translation Off

ATF-4, CHOP, mRNATranslation

Apoptosis, Changes in Metabolism & Redox Status

Global Translation On

Growth Factors, ER Stress,

Viral InfectiondsRNA

Unfolded ProteinResponse, Hypoxia Glucose Deprivation,

UV Light, Amino AcidStarvation

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 MAPKErk

PRAS40

p70 S6K

TSC1

TSC2

eIF4B

eIF4H

MNK

4E-BP1

4E-BP1

eIF4GeIF4EeIF4E

PTEN

PDK1

PI3KIRS-1

LKB1

AMPK

PABP

PABP

Akt

S6

p90RSK

eIF4F

eIF4F

eEF2K

PAIP1PAIP2

Hormones, Growth Factors, Cytokines, Neuropeptides Mitogens Stress

elF4A

PDCD4

Wnt

FrizzledLRP

Gαq/o Dvl

GRB10

RagA/BRagC/D

GSK-3

FKBP12

TBC1D7

mTORC2

mTORC1

43S

48S

Translation Off

Translation Elongation On

Translation On

rapamycin

Torin1PP242KU63794WYE354

AminoAcids

PIP3

Cap

AAAAA

AMP:ATP

mTORC2

mTORRictor

Sin1 PRR5

DEPTOR

RaptorGβLmTOR

DEPTOR

mTORC1

GβL

eEF2

Translational Control: Regulation of elF4E and p70 S6K© 2002–2015 Cell Signaling Technology, Inc.

Transcriptionally InactiveChromatin

Transcriptionally ActiveChromatin

SUV39h

MeHP1SUV

39h

MeHP1SUV

39h

MeHP1SUV

39h

MeHP1

MePCPRC1

MePCPRC1

MePCPRC1

MePCPRC1

Me

BPTF

NURF Me

BPTF

NURF

Me Me

Me

Me

Me

Me

Me

Me

Me

Me

MeMeMe

Me

Pericentric HeterochromatinInactive X ChromosomeRb-Mediated Repression

Pericentric Heterochromatin

Inactive X ChromosomeHox Gene Repression Anti-Silencing

Transcription Initiation

Transcription Elongation

Methylation

H3K9meDemethylation

Methylation

Demethylation

Methylation

H4K20me

Demethylation

Methyla

tion

H3K27

me

Demeth

ylatio

n

Methylation

H3K79me

Demethylation

Methyla

tion

H3K4m

e

Demeth

ylatio

n

H3K36me

H3K4meMethylases: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

H4K20meMethylases:SET8/KMT5A (+) NSD1/KMT3B (+,†)ASH1L/KMT2H (+,†,‡)SUV420H1/KMT5B (†,‡)SUV420H2/KMT5C (†,‡)NSD2/KMT3G (+,†)Demethylases:JHDM1D/KDM7A (+,†)PHF8/KDM7B (+,†)

H3K9meMethylases: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 (†,‡)

H3K27meMethylases:Ezh2/KMT6 (+,†,‡)NSD2/KMT3G (+,†,‡)NSD3/KMT3F (†,‡) Demethylases:JHDM1D/KDM7A (+,†)PHF8/KDM7B (+,†)UTX/KDM6A (†,‡)JMJD3/KDM6B (†,‡)

H3K36meMethylases:NSD1/KMT3B (+,†)SMYD2/KMT3C (+,†)NSD2/KMT3G (+,†)SET2/KMT3A (‡) Demethylases:JMJD1A/KDM2A (+,†)JMJD1B/KDM2B (+,†)JMJD2A/KDM4A (†,‡)JMJD2B/KDM4B (†,‡)JMJD2C/KDM4C (†,‡)JMJD2D/KDM4D (†,‡)KDM4DL/KDM4E (†,‡)

H3K79meMethylases:DOTIL/KMT4 (+,†,‡)Demethylases:???

Histone Lysine Methylation© 2002–2015 Cell Signaling Technology, Inc.

NcoR

Su Su

HDACNuRD

Sin3

TF

TFIIA

p53

TBPTFIID

TFIIH

RNA Pol IITFIIE

TFIIFTFIIB

CBP/p300

PCAF

SRC-3

TFTATA

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

RegulatorySignaling Pathways

Signaling Pathways

Fatty Acid SynthesisHistone Acetylation

Gluconeogenesis

Expression of Gluconeogenic Genes

NADPH

Cell Cycle

ProteinAcetylation

HistoneAcetylation

Cytoskeletal Regulation Ribosomal Proteins Chaperones

RNA Splicing

Deacetylation

BMP, Wnt, Notch

TranscriptionPluripotencyDevelopmentDifferentiation ofNeural Stem Cells

ATF-2CBPCDYCLOCKEWIElp3GCN5L2GRIPHAT1HBO1MCM3AP

AcetylTransferases

Acetylation

Nuclear Transport

Histones

Stability Stability

DNA Damage

DNA Damage Metabolism

DNARepair

HDAC ClassesClass I: HDAC1-3, 8Class II: HDAC4-7, 9, 10Class III: SIRT1-7Class IV: HDAC11

MORFMOZp300PCAFp/CIPSRC-1SRC-3hTAFII250TFIIBTip60

DeacetylasesAcetylases

Protein Acetylation© 2002–2015 Cell Signaling Technology, Inc.

Su

p53 p53 p53 CBP/p300

TIP60

MOF

Ub

UbUbUb

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

MEF2AResting Neurons

dissociation

dissociation

Transcription

Aurora B, Ras

K372

S20S20

K120K372

K381

K382

K372

K373

K381

K382

DNA Damage

p53 Ubiquitination/Degradation

Transcriptional Repression

Transcriptional Activation

p53 Stability/Transactivation ofpro-apoptotic target genes

Membrane Depolarization Ca+2

S408S408

Dendric ClawDifferentiation 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.