Role of gab-1 in the hgf, and egf signalling pathways

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Project objective

Research objectives and content MET, SEA and RON are tyrosine kinase receptors mediating cell growth, scattering and tubulogenesis. Cell scattering and tubulogenesis are not elicited by other tyrosine kinase receptors expressed in the same cells, such as the EGF receptor. However, the same set of proteins is activated in response to EGF and HGF and both tyrosine kinase receptors phosphorylate the same substrates such as GAB-I. Moreover, the overexpression of GAB-I in kidney epithelial cells results in constitutive and ligand-independent cell scattering and branching-morphogenesis. In contrast, overexpression of truncated-GAB- I containing only the MET binding domain strongly impaired the response to MET signals. These results indicate that activation of GAB-I alone is sufficient ffir the induction of the pleiotropic cellular responses which are characteristically seen after MET activation. Furthermore, in physiological conditions, the activation of a specific tyrosine kinase (HGF receptor versus EGF receptor) induce 'scattering', indicating that GAB-I phosphorylation triggered by one tyrosine kinase could be specific and lead to the generation of interaction sites for specific SH-2 domain-containing proteins. Hence recruitment of 'receptor kinase-specific' downstream signaling molecules could occur. The aims of the proposed study are: (i) to compare the behaviours towards GAB-I of HGF receptor versus EGF receptor; (ii) to analyze the role of GAB- I in the induction of HGFmediated-scattering response. Training content (objective, benefit and expected impact) The objective of the candidate is to broaden his experience and his knowledge in the research of receptor tyrosine kinases and intracellular signaling pathways. Moreover, the candidate will acquire training in the field of molecular biology and in the different biological assays used to analysis scattering and morphogenic responses.Providing his application for a fellowship is positively considered, it would be interesting and useful for him to join the Cancer Research Institute (I.R.C.C.) in Turin, Italy, under the direction of Professor Paolo Comoglio. These work experiences give the possibility to publish novel finding in journals of international reputation. Links with industry / industrial relevance (22)

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Participants

• UNIVERSITY OF TORINO · TORINO (TURIN)CoordinatorItaly

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