INTERACTION WITH THE PHOSPHOTYROSINE BINDING DOMAIN PHOSPHOTYROSINE INTERACTING DOMAIN OF SHC IS REQUIRED FOR THE TRANSFORMING ACTIVITY OF THE FLT4/VEGFR3 RECEPTOR TYROSINE KINASES/

The FLT4 gene encodes two isoforms of a tyrosine kinase receptor, whic h belongs to the family of receptors for vascular endothelial growth f actor. As the result of an alternative processing of primary mRNA tran scripts, the long isoform differs from the short isoform by an additio nal stretch of 65 amino acid residues located at the C terminus and co ntaining three tyrosine residues, Tyr(1333), Tyr(1337), and Tyr(1363). Only the long isoform is endowed with a transforming capacity in fibr oblasts. We show that this activity is related to the capacity of the tyrosine 1337-containing sequence to interact with the phosphotyrosine binding domain of the SHC protein. This demonstrates that a functiona l. property of this newly described domain includes relay of mitogenic signals. In addition, it shows that the same receptor can mediate dif ferent functions through the optional binding of the phosphotyrosine b inding domain and that the alternative use of this domain is sufficien t to direct the signal toward different pathways.