Lecture 30 Flashcards
What produces HGF?
Fibroblasts and other stromal cells
What does HGF bind to and what does this induce?
HGF binds to HGF Receptor or Met to induce receptor dimerization,
transphosphorylation of tyrosines 1234 and 1235 maximising enzymatic activity
Phosphorylation of C-termina tyrosines, and other substrates providing multifunctional docking sites for signalling molecules
What does HGF function in?
Embryonic development as it regulates growth, differentiation and epithelial morphogenesis
Adult tissue repair which induces cell detachment, shape change, invasion of damage site and regeneration
Cancer as it can drive invasive and metastatic growth, it was discovered as it induces motility in cultured cells causing them to scatter
How is abnormal HGF/HGFR signalling generated?
HGFR is over-expressed promoting spontaneous dimerization and tyrosine kinase activity.
Hypoxia
Gene amplification
Missense point mutations
Point mutations in the juxtamembrane domain
A positive autocrine loop
How does hypoxia induce over expression of HGF/HGFR?
Hypoxia inducible factor is induced, which activates transcription of the HGFR gene as the HGFR promter has a HIF-Binding site allowing ti to drive gene activation
How do missense point mutations induce abnormal HGFR signalling?
If the mutation is in the TK domain then there is an increase in kinase activity
For example Y1235D causes a permanent negative charge to mimick phosphotyrosine
Inherited HGFR mutations cause renal carcinomas
How do point mutations in the juxtamembrane domain drive abnormal HGFR signalling?
Prevents the binding of a ubiquitin ligase and therefor promotes protein retention, causing increased HGFR expression and signal transduction
How does HGF affect proliferation in cancer?
HGF signals Ras this activates a protein kinasecascade inducing transcription of genes involved in cellular proliferation including cyclin D1 which phosphorylates pRb and triggers entry into the cell cycle
How does HGF induce protection from apoptosis?
HGF signals phosphatidylinositol-3-kinase (PI3K) which induces PI3 phosphates in the plasma membrane leading to actovation and recruitment of Akt protein kinase which activates the antiapoptotic protein BCL-2 and phosphorylates the apoptotic procaspase 9 inhibiting its apoptotic effects
This makes the cell resistant to apoptosis and allows it to survive anoikis
How does HGF lead to angiogenesis?
HGF and Ras induce VEGF which leads to angiogenesis
How does HGF lead to scattering?
HGFR phosphorylates and disassembles adherens junctions, the Ras pathway uses Snail and Slug to prevent transcription of genes which code for adherens junction components
What are the three ways in which cancer cells scatter?
Mesenchymal motility
Collective motility
Amoeboid motility
What occurs in mesenchymal motility?
Slow movement
Activation of HGFR, leads to Ras which leads to PI3K causes F-actin to form at the leading edge of the cell causing the generation of actin rich protrusions and integrin dependant focal adhesions with the ECM. Large focal adhesions allow contractile force of actomyosins. Cell movement requires ECM degradation via secreted proteases
What occurs in Collective motility?
Cohort migration where sheets of cells move when stimulated by HGF
These cells demonstrate mesenchymal motility but retain adherens junctions, the leading cells trigger actin polymerisation and secret prtoeases as seen in mesenchymal Motility
What occurs in amoeboid motility?
Fast movement where chemoattractant receptors trigger actin polymerisation
Contraction then changes cell shape via hydrostatic pressure allowing the cell to squeeze through gaps
