The docking molecule Gab2 is induced by lymphocyte activation and is involved in signaling by interleukin-2 and interleukin-15 but not other common gamma chain-using cytokines

Interleukin (IL)-2, a critical cytokine with indispensable functions in reg ulating lymphoid homeostasis, induces the activation of several biochemical pathways. Precisely how these pathways are linked and how they relate to t he biological action of IL-2 is incompletely understood. We previously iden tified SHP-2 (Src homology 2 domain containing phosphatase 2) as an importa nt intermediate in IL-S-dependent MAPK activation and showed its associatio n with a 98-kDa phosphoprotein in response to IL-2. Were, we demonstrate th at Gaba, a recently identified adapter molecule, is the major SHP-2 and pho sphatidylinositol 31-kinase-associated 98 kDa protein in normal, IL-a-activ ated lymphocytes. We further demonstrate that phosphorylation of both Gab2 and SHP-2 is largely dependent upon tyrosine 338 of the IL-2 receptor beta chain. Gaba can be a substrate of all the three major classes of non-recept or tyrosine kinases associated with the IL-SR, but in terms of IL-2 signali ng, JAK3 but not Lck or Syk is essential for Gabs phosphorylation, We also demonstrate that only IL-2 and IL-15, but not other gamma c cytokines induc e Gabs phosphorylation; the ability to phosphorylate Gaba correlates with S hc phosphorylation and ERK1/ERK2 activation. Finally, we also show that Gab a levels are regulated by T cell activation, and resting T cells express li ttle Gaba. Therefore, up-regulation and activation of Gaba may be important in linking the IL-2 receptor to activation of MAPK and may be an important means of achieving specificity in cytokine signaling.