Gene Transcription G0G0 G1G1 Priming S G2G2 M Cell Cell Cycle Growth Factors + Growth Factors & Cell Cycle Receptors

TK EGFR Function in Normal Cell TK ATP Cell Proliferation Antiapoptosis Angiogenesis Gene Transcription Cell Cycle Progression +

TK EGFR signal transduction in tumour cells Survival (anti-apoptosis) PI3-K STAT3 AKT PTEN MEK Gene transcription MAPK Proliferation/ maturation Chemotherapy / radiotherapy resistance Angiogenesis Metastasis pY RASRAF SOS GRB2 pY G1G1 S M G2G2

Normal Cell Cancerous Cell Up Regulation Mutation Consequence of proliferation of EGFR receptors

TK Strategies to inhibit EGFR signaling EGFR tyrosine kinase inhibitors Anti-EGFR mAbs Anti-ligand mAbs Bispecific Abs Immune effector cell ATP

The PDGF-Receptor tyrosine kinase can bind several SH2-domain containing proteins simultaneously. 716 Tyr-P 1009 Tyr-P 763 Tyr-P 740 Tyr-P 1021 Tyr-P 771 Tyr-P Grb2 PI,3 kinase GAP Shp2 { { STAT Shc/Src 1043 Tyr-P PLC-  Ligand Binding Kinase Domain

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.