Efficient cellular transformation by the Met oncoprotein requires a functional Grb2 binding site and correlates with phosphorylation of the Grb2-associated proteins, Cbl and Gab1

The Tpr-Met oncoprotein consists of the catalytic kinase domain of the hepatocyte growth factor/scatter factor receptor tyrosine kinase (Met) fused downstream from sequences encoded by the tpr gene, Tpr-Met is a member of a family of tyrosine kinase oncoproteins generated following genomic rearrangement and has constitutive kinase activity, We have previously demonstrated that a single carboxyl-terminal tyrosine residue, Tyr(489), is essential for efficient transformation of Fr3T3 fibroblasts by Tpr-Met and forms a multisubstrate binding site for Grb2, phosphatidylinositol 3' kinase, phospholipase C gamma, SHP2, and an unknown protein of 110 kDa, A mutant Tpr-Met protein that selectively fails to bind Grba has reduced transforming activity, implicating pathways downstream of Grba in Tpr-Met mediated cell transformation, We show here that the 110-kDa Tpr-Met substrate corresponds to the recently identified Grb2-associated protein, Gab1, Moreover, we show that tyrosine phosphorylation of the Cbl protooncogene product as well as Gab1 required Tyr(489) and correlated with the ability of Tpr-Met to associate with Grba and to transform cells, providing evidence that pathways downstream of Gab1 and/or Cbl may Flay a role in Tpr-Met-mediated cell transformation.