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Gene Transcription. S. Growth Factors. +. Priming. G 1. G 0. G 2. Cell Cycle. M. Growth Factors & Cell Cycle. Receptors. ATP. ATP. TK. TK. +. EGFR Function in Normal Cell. Gene Transcription Cell Cycle Progression. Antiapoptosis. Cell Proliferation. Angiogenesis. TK. TK. - PowerPoint PPT Presentation
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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
STAT3AKTPTEN
MEK
Gene transcriptionMAPK
Proliferation/maturation
Chemotherapy /radiotherapyresistance
Angiogenesis Metastasis
pYpY
RAS RAFSOS
GRB2pY
G1
SM
G2
Normal CellCancerous CellUp Regulation
Mutation
Consequence of proliferation of EGFR receptors
TK TK TK TK
Strategies to inhibit EGFR signaling
-- -- -- --
EGFR tyrosine kinase inhibitors Anti-EGFR mAbs
Anti-ligand mAbs Bispecific
Abs
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
Grb2PI,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.