Manifestation of Novel Social Challenges of the European Union in the Teaching Material of Medical Biotechnology Master’s Programmes at the University of Pécs and at the University of Debrecen

Medical Biotechnology Master’s Programmes

at the University of Pécs and at the University of Debrecen

Identification number: TÁMOP-4.1.2-08/1/A-2009-0011

RECEPTOR

INTERACTIONS

SIGNALING CROSS- TALK

Tímea Berki and Ferenc Boldizsár Signal transduction

Medical Biotechnology Master’s Programmes

at the University of Pécs and at the University of Debrecen

Identification number: 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.

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!

Levels of signal “cross-talk”

• Cell surface receptors

• Plasma membrane proximal signaling complexes

• Cytoplasmic signaling complexes

• Pathway merging / branching

• Transcription factors

Glucagon Secretin Adrenaline

ACTH LH FSH

Adenylyl cyclase

ATP cAMP

More receptors using the same

second messenger system

Growth factor receptor – integrin signaling interaction

Integrins

Growth factors

Angiogenesis Invasion, proliferation Suppression of apoptosis

IBPs PTEN

ILK

PI3K IRS1 Nck2 Pinch

GSK3

LEF1

AP1 Cyclins Cadherins ECM

PKB

-catenin

+

-

-

- +

+

+

EGF signaling

EGFR

JNK SOS

Ras GRB2

C-Fos Raf

MAPKK

AP1

MAPK PAK1

Nck

GRB2

Gab1

Shp2

WASP Src

Shc

Bad FKHR

CREB

RSK2 p53 Jun

MAPK p38 JNK

Cdc42 /Rac Vav2

EGF

Cytoskeleton Cell cycle

Apoptosis

STAT1 STAT3

Target genes

ADAM

HB-EGF PTP

Rac H₂O₂

NADPH

synthesis 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

Ras GAP +

- -

- -

- +

- +

General characteristics of GF signaling

Diverse input signals (Multiple RTKs)

Conserved core processes

Diverse ouput events (transcriptional responses,

cytokeletal changes, etc) System control

+

- +

+ - Input layer

Output layer

Ras – an important signaling switch

P

P P P P

P P 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-pathway

B-RAF mutation: 1/4 EGFR- pathway

PTEN mutation: 1/4 EGFR pathway PI3K mutation: 1/4 EGFR pathway

EGFR

BcR and FcβRIIB cross-talk

SHIP FcRIIB

P a

BCR

Iga Ig

ITIM LYN

PLC

BTK

No membrane recruitment

RAS SHC DOK

Simultaneous cross-linking

Inhibition of calcium flux and proliferation

PIP

PIP

Non-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 z z

ZAP70 Lck

HSP90 a 



d e e z z

P

?

TCR TCR

TNFR – GR cross-talk I

GC

Plasma membrane

Cytoplasm

MAPK Chaperone

complex

GRE TFRE

TF

RNA Pol-II TFRE

TF

pTEF P

RNA Pol-II TFRE

TF

TFRE TF

TFRE TF

TFRE TF

AC AC

AC

HDAC2 TFRE

TF

MSK1

TFRE P TF

P 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 removal Chromatin modulation: HDAC recruitment

GR

Nucleus TF

MAPK inactivation

GILZ, MKP-1, TTP, IBa

TNF TNFR

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

TNF TNFR

TNF TNFR

ROS

GR TF

ROS

Transcription factor cross-talk

Composite RE

Oct-1 +

CREB +

Ets1 +

AP-1(cJun:cJun +

C/EBP –

AP-1(cJun:cFos) –

Lapping RE

TFIID –

Oct-1 –

TF-RE

AP-1 –

NF-kB –

PU.1/Spi-1 –

SMAD3,4 –

T-bet –

Oct1/2 –

STAT6 –

IRF3 –

COUP-TFII +

STAT5 +

GRE

AP-1 –

NF-B –

PU.1/Spi-1 –

STAT5 –

COUP-TFII –

T-bet –

SMAD6 –

Oct1/2 +

+ : Induction of transcription

– : Inhibition of transcription

Convergence of signaling pathways

Growth Cytokines

↓Apoptosis

Apoptosis Other products Proliferative phenotype Nuclear Transription Factors

Gene activation or repression

Elastase Tenascin-c Cell surface receptors

NO restores hypoxia blocks

Virus infection?

HIV, HHV-8

VEGF Endothelin Angiopoiethin

ALK/End or BMPR 1-2 BMPs or

TGF

EGF TNFa

ANG II PDGF 5HT (serotonin)

Anorexigens

Estrogen 5HT transporter

K⁺ channels Platelets

Circulating cells and mediators

Intracellular signalling

Apoptosis SMC tone ERK

JNH

SMADs

MAP Kinases

ES Receptor KDR

B A

TIE

AML O^-₂

NO

G protein P