Gene Transcription

G0G1

Priming

S

G2

M

Cell Cell Cycle

Growth Factors

++

Growth Factors & Cell Cycle

Receptors

TK

EGFR Function in Normal Cell

TKATP ATP

Cell Proliferation Antiapoptosis

Angiogenesis

Gene Transcription

Cell Cycle Progression

+

TKTK

EGFR signal transduction in tumour cells

Survival(anti-apoptosis)

PI3-K

STAT3

AKTPTEN

MEK

Gene transcriptionMAPK

Proliferation/maturation

Chemotherapy /radiotherapyresistance

Angiogenesis Metastasis

pYpY

RAS RAFSOS

GRB2pY

G1

SM

G2

Normal CellCancerous Cell

Up Regulation

Mutation

Consequence of proliferation of EGFR receptors

TK TK TK TK

Strategies to inhibit EGFR signaling

---- -- --

EGFR tyrosine kinase inhibitors

Anti-EGFR mAbsAnti-ligand

mAbs BispecificAbs

Imm

une

effector cell

ATP

The PDGF-Receptor tyrosine kinase can bind several SH2-domaincontaining proteins simultaneously.

716Tyr-P

1009Tyr-P

763Tyr-P

740Tyr-P

1021Tyr-P

771Tyr-P

Grb2

PI,3 kinaseGAP

Shp2

{

{STAT

Shc/Src

1043Tyr-P PLC-

Ligand Binding

KinaseDomain

The MAP Kinase (Extracellular-Related Kinase ERK) Cascade

Mitogens, Growth Factors

Ras

RAF

MAPK

MAPKK/MEK1

MAPKKK

MAP4K

MAP3K

MAP2K

MAPK

GTPase

Transcriptional Regulation

Cytokines, Cell Stress

Rac, Cdc42

MEKK1

PAK

JNKK/SEK

JNK

}

Cytosol

Nucleus

Raf

Background Information

What is PDGF?

It is also known as platelet-derived growth factor.

There are four types of ligands: PDGFA, B, C, and D.

PDGF ligands are homodimers.

If there are PDGF, there must be PDGFRs

Three types of receptors: PDGFR alpha alpha, alpha beta, and beta beta.

PDGFRB’s Functions in Cellular Level

Receptor tyrosine kinase.

Ligand binding-> dimerization-> autophosphorylation.

Activates the Ras-MAPK, PI3K, & phospholipase C gamma pathways.

PDGFR Activation Pathways

Hoch & Soriano (2003) Development 130:4772

What does PDGFRB do for the organism?

PDGFR + PDGF regulate development of vascular smooth muscle cells

Mice lacking PDGF or PDGFR die perinatally with extensive hemorrhaging.