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.
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