EN-BLOC SUBSTITUTION OF THE SRC HOMOLOGY REGION-2 DOMAIN ACTIVATES THE TRANSFORMING POTENTIAL OF THE C-ABL PROTEIN TYROSINE KINASE

Src homology region 2 (SH2) domains are present in many proteins invol ved in signal transduction. In nonreceptor protein tyrosine kinases th e SH2 domain has been implicated in regulation of tyrosine kinase acti vity and in mediating interactions involved in downstream signaling. D ifferent SH2 domains exhibit distinct binding specificities for both p hosphotyrosine- and phosphoserine/phosphothreonine-containing proteins . We show that different SH2 domains are not functionally equivalent w ithin the context of the c-ABL1b protooncogene. c-ABL1b, altered by re placement of its SH2 domain with the N-terminal SH2 domain of Ras GTPa se-activating protein, exhibited activated transforming capability, ca used intracellular tyrosine phosphorylation of p62, and was relocalize d from nucleus to cytoplasm. This en bloc substitution apparently unco uples two distinct functions of the SH2 domain so that c-ABL escapes n ormal regulatory control while it retains the capability to elicit sig nals that promote transformation. The SH2 domain of the ARG protein ty rosine kinase, which shares high amino acid-sequence homology with the SH2 domain of ABL, was less effective in activating the oncogenic pot ential of c-ABL. The effects that the N-terminal SH2 domain of Ras GTP ase-activating protein has in the context of c-ABL resemble the effect s of deleting the SH3 domain. Thus, the SH2 and SH3 domains may have c oordinate roles as regulatory control elements within the context of c -ABL.