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.