Cloning of p97/Gab2, the major SHP2-binding protein in hematopoietic cells, reveals a novel pathway for cytokine-induced gene activation

Several components in cytokine signaling remain unidentified. We report the cloning and initial characterization of one such component, p97, a widely expressed scaffolding protein distantly related to Drosophila DOS and mamma lian Gab1. Upon cytokine, growth factor, or antigen receptor stimulation, p 97 becomes tyrosyl phosphorylated and associates with several SH2 domain-co ntaining proteins, including SHP2. Expression of p97 mutants unable to bind SHP2 blocks cytokine-induced c-fos promotor activation, inhibiting Elk1-me diated and STAT5-medieted transactivation. Surprisingly, such mutants do no t inhibit MAPK activation. Our results identify p97 as an important regulat or of receptor signaling that controls a novel pathway to immediate-early g ene activation and suggest multiple functions for SHP2 in cytokine receptor signaling.