ACTIVATION OF EXTRACELLULAR SIGNAL-REGULATED KINASE-2 BY A NOVEL ABL BINDING-PROTEIN, ST5

The human ST5 gene encodes three proteins with predicted molecular mas ses of 126, 82, and 70 kDa. These widely expressed proteins share a C- terminal region that bears significant sequence homology to a group of GDP/GTP exchange proteins for the Rab3 family of small GTP binding pr oteins. The N-terminal region of the largest ST5 protein, p126, contai ns two proline-rich sequences, PR1 and PR2, with consensus motifs simi lar to Src homology 3 (SH3) binding regions and to mitogen-activated p rotein kinase (MAPK) phosphorylation sites. Based on these properties, we sought to investigate the activity of ST5 proteins in signal trans duction pathways, In vitro, p126 displayed preferential binding to c-A bl SH3, as compared with other SH3 domains. This interaction was media ted by the PR2 sequence. In vivo, expression of p126, but not p82 or p 70, activated MAPK/ERK2 in response to EGF in COS-7 cells. Expression of c-Abl with p126 greatly enhanced this activity. Deletion of PR1 blo cked the ability of p126 to activate ERK2. Deletion of PR2 did not aff ect the basal activity, but blocked the stimulatory effect of c-Abl. W hereas p82 expression had no effect on ERK2 activation by p126, p70 co mpletely abrogated this activity. These observations suggest that ST5 can function as a signaling protein and can provide a link between c-A bl and ERK2.