Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat the University of Pécs and at the University of DebrecenIdentification number: TÁMOP-4.1.2-08/1/A-2009-0011

RECEPTOR INTERACTIONS SIGNALING CROSS-TALK

Tímea Berki and Ferenc BoldizsárSignal transduction

Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat the University of Pécs and at the University of DebrecenIdentification number: TÁMOP-4.1.2-08/1/A-2009-0011

TÁMOP-4.1.2-08/1/A-2009-0011

Introduction• Although there is a need for the precise

separation of certain pathways to maintain the specificity of signals, upon complex physiological stimuli more pathways might be active in parallel. This creates a basis for interaction between active pathways.

• Signaling pathways form a “network”.• Some proteins can participate in multiple

pathways.

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Mechanisms of interaction• Synergism/antagonism• Direct protein interactions – large signaling

complexes, organized by scaffold proteins and the cytoskeleton

• Phosphorylation/dephosphorylation• Importance: when targeting a pathway never

forget about potential interactions with other pathways!

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Levels of signal “cross-talk”• Cell surface receptors• Plasma membrane proximal signaling

complexes• Cytoplasmic signaling complexes• Pathway merging / branching• Transcription factors

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GlucagonSecretin AdrenalineACTH LH FSH

Adenylyl cyclase

ATP cAMP

More receptors using the same second messenger system

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Growth factor receptor – integrin signaling interaction

Integrins

Growth factors

Angiogenesis Invasion, proliferationSuppression of apoptosis

IBPs

PTEN

ILK

PI3KIRS1

Nck2Pinch

GSK3

LEF1

AP1 Cyclins Cadherins

ECM

PKB-catenin

+

-

-

-+

+

+

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EGF signaling

EGFR

JNK

SOS

Ras

GRB2

C-Fos

Raf

MAPKK

AP1

MAPK

PAK1

NckGRB2

Gab1

Shp2

WASP

Src

Shc

Bad FKHR

CREB

RSK2 Junp53

MAPK JNKp38

Cdc42/Rac

Vav2

EGF

CytoskeletonCell cycle

Apoptosis

STAT1 STAT3

Target genes

ADAM

HB-EGF

PTP

Rac

H2O2

NADPHsynthesis Gab1

PI3K

PIP3

E2Ub

Targets

DOK

Akt PDK1

Cbl

MKK2 MKK4

MEKK MEKK4

Rac

FAK

CAS

Paxillin

Src

Targets

Ca2+

PKC

DAG

PLC

IP3

MAPK

RasGAP

+

- -

- -

-

+

-

+

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General characteristics of GF signaling

Diverse input signals(Multiple RTKs)

Conserved coreprocesses

Diverse ouput events(transcriptional responses,cytokeletal changes, etc)

System control+

- +

+

-

Input layer

Output layer

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Ras – an important signaling switch

P

PP

PP

PP

P

SOS

Erk

GRB2

Ras

BRaf

PI3K3R1

PI3K3CA

Akt

mTOR

PTEN

PLCe PLC

PKC

JAK

STAT1/3

RAS-independent

K-RAS mutation controls 75% of EGFR-pathwayB-RAF mutation: 1/4 EGFR-pathwayPTEN mutation: 1/4 EGFR pathwayPI3K mutation: 1/4 EGFR pathway

EGFR

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BcR and FcβRIIB cross-talk

SHIP

FcRIIB

P

a

BCR

Iga Ig

ITIMLYN

PLCBTK

No membrane recruitment

RAS

SHCDOK

Simultaneous cross-linking

Inhibition of calcium flux and proliferation

PIP3PIP2

TÁMOP-4.1.2-08/1/A-2009-0011Non-genomic GR signaling – interaction of GR with cytoplasmic TcR signaling proteins• Heat shock proteins (chaperons) organize multiprotein

complexes• GR associates with Hsp-90 and ZAP-70

HSP90

Plasma membrane

Cytoplasm

a

d e e zz

ZAP70

Lck

HSP90

a

d e e zz

ZAP70

Lck

P

?

TCR TCR

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TNFR – GR cross-talk IGC

Plasma membrane

Cytoplasm

MAPK

Chaperone complex

GRE TFRE

TF

RNA Pol-II

TFRE

TFpTEF P

RNA Pol-II

TFRE

TF

TFRE

TF

TFRE

TF

TFRE

TFAC

ACAC

HDAC2

TFRE

TFMSK1

TFRE

TFPP

H3

MSK1

TFRE

TF

H3

Inhibition of RNA Pol-II phosphorilation Cofactor competition

Induction of anti-inflammatory genes Tethering of pro-inflammatory TF

Chromatin modulation: MSK1 removalChromatin modulation: HDAC recruitment

GR

Nucleus

TFMAPK inactivation

GILZ, MKP-1, TTP, IBa

TNFTNFR

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TNFR – GR cross-talk II

Plasma membrane

Cytoplasm

MAPK

GRE

HDAC2

TFRE

TF

Cofactor competition

Transcription factors like:NFkB, AP-1, IRFs,...

GC

GR

Nucleus

TF

TNFTNFR

TNFTNFR

ROS

GR TF

ROS

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Transcription factor cross-talk

Composite REOct-1 +CREB +Ets1 +AP-1(cJun:cJun +C/EBP –AP-1(cJun:cFos) –

Lapping RETFIID –Oct-1 –

TF-REAP-1 –NF-kB –PU.1/Spi-1 –SMAD3,4 –T-bet –Oct1/2 –STAT6 –IRF3 –COUP-TFII +STAT5 +

GREAP-1 –NF-B –PU.1/Spi-1 –STAT5 –COUP-TFII –T-bet –SMAD6 –Oct1/2 +

+ : Induction of transcription– : Inhibition of transcription

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Convergence of signaling pathways

GrowthCytokines

↓Apoptosis

Apoptosis Other products Proliferativephenotype

Nuclear Transription Factors

Gene activation or repression

ElastaseTenascin-c

Cell surface receptors

NO restoreshypoxia blocks

Virus infection?HIV, HHV-8

VEGF

Endothelin

Angiopoiethin

ALK/End orBMPR 1-2

BMPs orTGF

EGFTNFaANG II PDGF 5HT (serotonin)

Anorexigens

Estrogen

5HT transporter

K+ channels

PlateletsCirculating cells and mediators

Intracellularsignalling

ApoptosisSMC tone

ERKJNH

SMADsMAP

Kinases

ES Recepto

rKDR

BA

TIE

AML

O-2

NO

G proteinP