SH2-CONTAINING PHOSPHOTYROSINE PHOSPHATASE SYP IS A TARGET OF P210BCR-ABL TYROSINE KINASE

The phosphorylation of proteins at tyrosine residues is critical in ce llular signal transduction and neoplastic transformation. These mechan isms are regulated by the activities of both protein-tyrosine kinases and protein-tyrosine phosphatases. Recent studies have identified a no vel protein-tyrosine phosphatase, termed Syp, that is widely expressed in various tissues. Syp encodes a cytoplasmic phosphatase that contai ns two Src homology 2 (SH2) domains. Since SH2 domains have been shown to target the association of signal transducing molecules to activate d tyrosine kinases, experiments were performed to determine whether Sy p might form specific complexes with p210bcr-abl, a fusion protein bel ieved to be involved in the pathogenesis of chronic myelogenous leukem ia and, thus, possibly alter or mediate p210bcr-abl tyrosine kinase ac tivity. We found that Syp was highly and constitutively tyrosine phosp horylated in three different murine cell lines transfected with a p210 bcr-abl expression vector. Furthermore, p210bcr-abl, Syp, and Grb2 for med stable complexes in BCR-ABL expressing cells. Complex formation be tween p210bcr-abl and Syp was mediated in vitro by the NH2-terminal SH 2 domain of Syp. Last, p210bcr-abl tyrosine kinase was effectively dep hosphorylated by Syp in vitro. These results suggest an interaction be tween Syp and BCR-ABL protein, which might play a role in cellular tra nsformation of BCR-ABL.