Uncoupling of Grb2 from the Met Receptor In Vivo Reveals Complex Roles in Muscle Development (original) (raw)

Abstract

homozygous mutant embryos, the liver is reduced in and Carola Ponzetto † size and shows extensive loss of parenchymal cells *European Molecular Biology Laboratory (Schmidt et al., 1995). Furthermore, consistent with the Meyerhofstrasse 1 scattering activity of HGF, Met-deficient embryos lack 69117 Heidelberg muscles of the limbs, diaphragm, and tip of the tongue, Federal Republic of Germany all deriving from migratory precursors (Bladt et al., 1995). † Department of Biomedical Sciences and Oncology Considerable progress has been made in understand-University of Torino ing the mechanism of Met signaling in cultured cells. 10126 Torino We have previously shown that the biological activity of Italy the receptor depends on the presence of two phospho-‡ International Institute of Genetics and Biophysics tyrosines (Y1349VHVNATY1356VNV) in the carboxy-terminal via G. Marconi 12 tail, which act as multifunctional docking sites for SH2-80125 Napoli containing effectors and activate an array of transduc-Italy tional pathways (Ponzetto et al., 1994). The Y 1356 VNV § Institute for Cancer Research motif, in particular, binds Grb2 (Songyang et al., 1993) 10060 Candiolo (Torino) and links the receptor with Ras. Mutation of Y 1356 alone Italy interferes heavily with all Met-mediated events, whereas mutation of Y 1349 has only a limited effect on transformation and no effect on motility. Mutation of both tyrosines Summary completely abrogates Met function (