Gab2, a new pleckstrin homology domain-containing adapter protein, acts touncouple signaling from ERK kinase to Elk-1

We describe a novel human adapter molecule containing a pleckstrin homolgy (PH) domain at the N terminus that is closely related to human Grb2-associa ted binder 1, Gab1, and Drosophila daughter of sevenless, We designate this protein as Gab2. Northern blot analysis indicates that Gab2 is widely expr essed and has an overlapping but distinctive expression pattern as compared with Gab1, with high levels of Gab2 mRNA detected in the heart, brain, pla centa, spleen, ovary, peripheral blood leukocytes, and spinal cord. Upon ty rosine phosphorylation, Gab2 physically interacts with Shp2 tyrosine phosph atase and Grb2 adapter protein. Strikingly, Gab2 has an inhibitory effect o n the activation of Elk-1-dependent transcription triggered by a dominant a ctive Ras mutant (RasV12) or under growth factor stimulation, whereas Gab1 acts to potentiate slightly the Elk-1 activity in the same system. In contr ast to the reciprocal effects of Gab1 and Gab2 in mediating Elk-1 induction , these two molecules have a similar function in extracellular signal-regul ated kinase activation induced by either oncogenic Pas or growth factor sti mulation. Taken together, these results argue that Gab1 and Gab2, two close ly related PH-containing adapter proteins, might have distinct roles in cou pling cytoplasmic-nuclear signal transduction, This is the first evidence t hat an intracellular molecule with a PH domain operates as a negative effec tor in signal relay to the regulation of gene expression.