mitogens

Factors that stimulate quiescent cells to proliferate

properties of quiescent cells

metabolically less active than proliferating cells

EGF

epidermal growth factor from epithelial cells

PDGF

Platelet-Derived Growth Factor� fibroblasts, smooth muscle cells.

VEGF

Vascular Endothelial Growth Factor - endothelial cells

Antigens

B-lymphocytes or T-lymphocytes that can react with the antigens.

Wnt

tissue stem and progenitor cells (hematopoietic stem cells,
intestinal crypt stem cells, skin stem cells).

Receptor Tyrosine Kinases

Growth Factor Receptors with Tyrosine Kinase Activity
� N-terminal extracellular ligand binding domain
� Single transmembrane alpha helix
� C-terminal intracellular protein tyrosine kinase catalytic domain

Five general mechanisms/types of mutations that lead to deregulated
mitogenic signaling

1) Gene amplification/overexpression
Example - Increase the amount of stimulating ligand, receptor or
signaling effector
2) Loss of gene expression of homeostatic effector
Example � Genetic loss of regulator protein that inhibits mitogenic signaling
3) Gene truncation that leads to a truncated protein
Example � Loss of extracellular ligand binding domain
4) Gene fusion that leads a chimeric protein
Example � Replacement of extracellular ligand binding domain with
another domain that leads to constitutive dimerization
5) Activating of inactivating point mutations in receptors or effectors
Example � Ras mutations that inactivate GTPase activity

Gain of RTK, Ras, or Raf function in what % of Human Cancers

about 85%

What happens when EGF binds to EGFR

EGF-binding induces EGFR dimerization, kinase activation and tyrosine
phosphorylation of C-terminal region of the receptor molecule

What does the truncation of EGFR do?

leads to loss of the ligand binding domain is observed in the
retroviral v-ErbB

RTK Mutations or Overproduction

Lead to Ligand-Independent RTK Dimerization and Kinase Activation in
Cancer Cells

Fusion of intracellular domains of EGFR to dimerization domains of
other receptor proteins can result in

mitogenic signaling activation

Transphosphorylation of tyrosines (pY) on RTKs creates

a binding motif for SH2 domain containing proteins (like Grb2) whose
SH3 domains bind SOS, a GEF of Ras

Truncation of EGFR leads to

loss of the ligand binding domain is observed in the retroviral
v-ErbB. Leads to constitutive firing

Fusion of intracellular domains of EGFR to dimerization domains of
other receptor proteins can result in

mitogenic signaling activation
Fig and Ros (RTK) dimerization causes constitutive firing

Binding of SH2 containing protein to phosphorylated-receptor
localizes other signaling proteins to membrane where they may be:

1. phosphorylated
2. catalytically activated
3. allowed to interact with other key signaling proteins

SH3: Src-Homology-3 domain.

Found in a variety of Enzymes and adaptor proteins. It binds to short
Peptide sequence rich in Proline residues.

SH2: Src-Homology-2 domain.

Found in a variety of Enzymes and adaptor proteins. It binds to short
Peptide sequence with a phosphotyrosine (p-Tyr, pY).

how many binding sites in SH2?

two. one binding site for phosphotyrosine and one binding site for
specific AA sequence

ket effector for RTK signaling

Ras