Shc associates with the IL-3 receptor beta subunit, SHIP and Gab2 following IL-3 stimulation: Contribution of Shc PTB and SH2 domains

p46(Shc) and p52(Shc) become heavily tyrosine phosphorylated in response to interleukin 3 (IL-3) treatment. We have investigated the potential of Shc to integrate IL-3 signalling pathways and demonstrate that Shc associates w ith the beta subunits of the human (beta c) and murine (Aic2A) IL-3 recepto rs, SHIP and Gab2 following IL-3 stimulation. The interaction between Shc a nd the IL-3 receptor beta chains was direct, mediated by both the SH2 and P TB domains. Interaction with SHIP was via the Shc PTB domain and the Shc SH 2 domain mediated the interaction with Gab2. Phosphopeptide competition stu dies suggest that the SH2 domain interacts primarily with tyrosine 612 of b eta c (610 of Aic2A), and the PTB domain with tyrosine 577 of beta c (575 o f Aic2A). PTB binding to IL-3R beta chains was of highest affinity, and app eared to play the primary role in binding. These findings suggest that Shc may play an important role in coordinately integrating IL-3 signalling path ways. (C) 2000 Elsevier Science Inc. All rights reserved.