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CST Signaling PaThway DiagramS for

Development and Differentiation

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Direct Stimulatory Modification

Direct Inhibitory Modification

Multistep Stimulatory Modification

Multistep Inhibitory Modification

Tentative Stimulatory Modification

Tentative Inhibitory Modification

Separation of Subunits or Cleavage Products

Joining of Subunits

Translocation

Transcriptional Stimulatory Modification

Transcriptional Inhibitory Modification

Kinase

Phosphatase

Transcription Factor

Caspase

Receptor

Enzyme

pro-apoptotic

pro-survival

GAP/GEF

GTPase

G-protein

Acetylase

Deacetylase

Ribosomal subunit

Angiopoietin 1

Angiopoietin 2

bFGF

Ephrin

PDGF

SLIT

VEGF

4E-BP1

Ets2

HIF-1α

HIF-1α

HIF-1α

HIF-1α HIF-1β

HIF-1β

PHDs

CBP/p300

MMPs

MMPs

PDGFR

Tie2VEGFR2

FGFR

Integrins Integrins

Neuropilin

Stat3Target Genes

Target GenesHRE

Normoxia

Hypoxia

Precursor Endothelial Cell

Platelet

Tip Cell

PericyteEndothelial

Cell

BasementMembrane

Tumor Associated Macrophage (TAM)

• Growth Factors• Cytokines• ECM Proteases

elF4E1

Erk1/2Akt

OH

OH

NucleusTumor CellTumor Cell

Tie2

EPH

ROBO1/2

ROBO3

• Growth Factors• Cytokines• ECM Proteases

Angiogenesis Signaling in Tumor Neovascularization© 2008–2015 Cell Signaling Technology, Inc.

NICD

NucleusCytoplasm

Frizzled

Gαq/o

Erk1/2

Nanog

NICD

Sox2Oct-4

TCFs

Erk1/2

Ras/Raf

Gene Expression

Pluripotency and Self RenewalhESC markers:

Gene Expression Gene Expression

Akt

Smad2/3

Smad2/3

Smad2/3Smad2/3

Smad2/3β-catenin

β-catenin

β-catenin Smad4

Smad4

Smad1/5/9

Smad1/5/9

Smad1/5/9

Smad1/5/9

Smad4

Smad1/5/9

PI3K

IGF-IRFGFR

TGF-β/Activin/NodalBMP

MEK1/2

PP2A

LRP

Wnt

SARA

AxinAPC

GSK-3

γ−Secretase

Polycomb

Oct-4 Sox2 NanogSSEA3/4 TRA-1-60 TRA-1-81

DifferentiationEndoderm MesodermEctoderm Primordial Germ Cells

Notch

ESC Pluripotency Differentiation© 2009–2015 Cell Signaling Technology, Inc.

ZO-2

AMOT

AMOT

AMOT

WBP2

β-TrCP

FRMDMerlin

KIBRA

SAV114-3-3 MARK4α-catenin

p73 RUNX

Mst1/2

SIK1-3

CK1

Rho

LKB1

LATS1/2MOB1 F-actin

ITCH

VGL4

Ajuba

YAP/TAZ

YAP/TAZ

YAP

14-3-3

YAP

TEAD1-4TEAD1-4 Smad

RASSFTAOK-1-3

PP2A

PP1

ASPP2

Merlin

Gα12/13

Gαq/11

Gαi/o

Gαs

FAT4 ?

??

CD

44

Crb

Transcription

Nucleus

Cytoplasm

Adhe

rens

Jun

ctio

nTi

ght J

unct

ion

GPCR Signaling Mechanical Signaling

YAP/TAZ

YAP/TAZ YAP/TAZYAP/TAZYAP/TAZ

Hippo Signaling© 2010–2015 Cell Signaling Technology, Inc.

Smad2/3TRAF4/6

USP4/11/15

PP2A

ROCK

PI3K

Akt

mTOR

CBP

Smad4

Smad7

Smad1/5/9Smad1/5/9

Smad4Smad2/3Smad2/3

Smad6/7

Smad2/3

RasSOS

Erk1/2

Smad1/5/9

Smad1/5/9

Smad4

Smad4Smad2/3

Smad2/3CBPSmad4

Smad1/5/9Smad1/5/9

JNK

TAK1

p38 NF-κB

JNKp38TAK1

TGF-β Ligands:TGF-βs, Activins, Nodals BMP Ligands:

BMP-2, -4, -7, MIS

Par6

SARA

RhoA

Smurf2

Smad7

TMEPAIRac/Cdc42

PKC

mDia PAK

MLC LIMK

Cofilin

c-Abl

Smurf1

Smurf1

TF TF

LIMK

Cofilin

p70 S6K

GRB2Shc

4E-BP1/2

Smurf2

Type I ReceptorType II Receptor

Type I ReceptorType II Receptor

Actin PolymerizationStress Fibers

Transcription Factors:AP-1 bZIP homeodomainRUNX Sp1 nuclear receptorsFox IRF-7 bHLH

Corepressors:c-Ski/SnoN Evi1HDAC4/5 TGIFTob (BMP only) SIP1

Coactivators:CBP/p300 SMIFMSG1 ARC105

Cell AdhesionActin Polymerization

Stress Fibers

NucleusCytoplasm

TGF-β Signaling© 2003–2015 Cell Signaling Technology, Inc.

WTXTAB1

TAB2

SFRP SFRPWIFPorc

WLS

WntDKKs

R-spondins

Frizzled Frizzled

APC

β-TrCP

Groucho

ICATChibby

LEF1/TCF1

Dvl

Dvl

Naked

RNF43ZNRF3

LGR5/6

PAR-1

LRP5

/6

Axin

Axin

PP2A

TCF3

Brg1Pygo BCL9

α-catenin

p120

LRP5

/6

Groucho

FoxO

Snail1TAZ

FoxO

Skp

β-catenin

β-catenin

β-catenin

CYLDTankyrase

HDAC

CBP

β-catenin

NLK

NLK

Rac1

GSK-3

GSK-3

β-catenin

TAK1

ub

Cadherin

CK1

CK1

ub

β-catenin

HDAC

β-catenin

ub

OFF

Hesx1

Target Genes: Myc, Cyclin D1, TCF-1, PPAR-δ, MMP-7, Axin-2, CD44, etc.

ON-StateOFF-State

NucleusCytoplasm

Migration

Adhesion

ProteasomalDegradation

Pit1

Wnt/β-Catenin Signaling© 2003–2015 Cell Signaling Technology, Inc.

ub

ub

ubub

ub

NEDD4

Neur or Mib

ADAM/TACE

Epsin

NICD

TM

InactiveLigand

ActiveLigand

γ-SecretaseComplex

Deltex

α-AdaptinNUMB

FBX7

SHARP

HDACKDM5A KDM5A

CtBP1 CIR

SMRTSKIPCSL

SKIPCSLMAML

HAT

Notch Target GenesHES FamilyMycp21Cyclin D3

NicastrinPresenilin

APH-1PEN-2

Inactive Active

S1 Cleavage

S2 Cleavage

S3 Cleavage

SignalReceiving

Cell

ExtracellularSpace

SignalSending

Cell

Furin

O-Fut

Golgi

Fringe

ER

NotchNotch

DeltaJagged Delta

Jagged

Nucleus

Ligand-receptor Internalization

Endosome

Endosome

LigandRepositioning

Recycling

LysosomalDegradation

UbiquitinDegradation

ActivatedReceptor

Cytoplasm

Notch Signaling© 2006–2015 Cell Signaling Technology, Inc.

SUFU

GLI 1/2/3

SUFU

GLI 1/2/3

SUFU

PKA

CK1

GSK-3β

β−TrCP

GLI 1/2/3

GLI 3-R

GLI 1/2/3GLI 1/2-Act

GLI 1/2-ActCyclin D, Cyclin E,Myc, GLI1, PTCH1,PTCH2, Hhip1

HhN

HhN

Hh

Skn

DISP1

ER/Golgi

Hh Secreting Cell

PTCH1

PTCH2

Nucleus

no transcription oftarget genes

Nucleus CytoplasmCytoplasm

Activator

Repressor

SMO

SMOProteasome

PrimaryCilium

PrimaryCilium

CDON/BOC

Shh

KCTD11

β-Arrestin

Dhh

Ihh

MammalianLigands:

Hhip1 GAS1

PTCH1

CDON/BOC MicrotubulesMicrotubules

GLI 3-R

KIF7KIF7

SCUBE2

GLI 1/2 Degradation

HhNGαi

Off-State On-State

Hedgehog Signaling© 2006–2015 Cell Signaling Technology, Inc.