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The HGF receptor family: unconventional signal transducers for invasive cell growth
1Institute for Cancer Research, University of Torino Medical School, Italy.
Abstract:
The HGF receptor family includes tyrosine kinases encoded by three oncogenes: MET, SEA and RON. The members of this gene family share a unique functional feature: they mediate cell dissociation and motility ('scattering') in physiological conditions, and invasiveness in their activated versions. The Met, Ron and Sea receptors display a distinctive signal transduction behaviour. Unlike conventional growth factor receptors, their cytoplasmic tails contain a multifunctional docking site. Upon autophosphorylation, this sequence simultaneously binds and activates multiple SH2-containing transducers, including Ras and PI 3-kinase. A deregulated activation of this 'supersite' triggers a dramatic pleiotropic signal which is responsible for invasive cell growth.
Insights
The MET, SEA, and RON receptor tyrosine kinases regulate cell motility and invasiveness. Their unique signaling mechanism involves a multifunctional docking site activating multiple pathways, leading to invasive cell growth when deregulated.
Area of Science:
- Molecular Biology
- Cell Biology
- Oncology
Background:
- The HGF receptor family comprises MET, SEA, and RON tyrosine kinases.
- These receptors are involved in cell dissociation, motility, and invasiveness.
Purpose of the Study:
- To elucidate the unique signal transduction mechanism of MET, SEA, and RON receptors.
- To understand how deregulated activation of these receptors contributes to invasive cell growth.
Main Methods:
- Analysis of receptor tyrosine kinase signaling pathways.
- Investigation of protein-protein interactions mediated by SH2 domains.
- Study of downstream signaling effectors like Ras and PI 3-kinase.
Main Results:
- MET, SEA, and RON receptors possess a multifunctional docking site in their cytoplasmic tails.
- This site binds and activates multiple SH2-containing transducers, including Ras and PI 3-kinase, upon autophosphorylation.
- Deregulated activation of this 'supersite' results in pleiotropic signaling driving invasive cell growth.
Conclusions:
- The HGF receptor family utilizes a unique signaling mechanism distinct from conventional growth factor receptors.
- Aberrant activation of the MET, SEA, and RON signaling 'supersite' is a key driver of invasive cancer phenotypes.