Abl binds JLP and cooperates with JLP and Cdo to activate p38 MAPK. (A and B) Lysates of 293T cells transiently transfected with Abl, S epitope-tagged JLP, or control (−) expression vectors, as indicated, were immunoprecipitated (IP) with anti-S epitope agarose beads (A) or Abl antibodies (B) and then Western blotted (WB) with S epitope or Abl antibodies. Straight lysates were also Western blotted with these antibodies. (C) Lysates of C2C12 cells that were proliferating in GM (G), at near confluence (0), or in DM for the indicated times were immunoprecipitated with antibodies to Abl and Western blotted with JLP or Abl antibodies. Straight lysates were also Western blotted with JLP, Abl, MHC, and pan-cadherin antibodies. (D) Lysates of 293T cells transiently transfected with HA-tagged p38, S epitope-tagged JLP, Abl, Abl-KD, Cdo, or control (−) expression vectors, as indicated, were Western blotted with pp38, HA epitope (p38), S epitope (JLP), Abl, and Cdo antibodies. (E) Model of p38 MAPK activation by Cdo-containing cell surface complexes. During myogenic differentiation, Bnip-2/Cdc42 complexes and JLP/p38 complexes bind to the Cdo intracellular region, resulting in Bnip-2/Cdc42-dependent activation of p38 by a pathway whose intermediates are yet to be identified. Active p38 phosphorylates substrates that contribute to muscle-specific transcription, including Mef2, E47, and BAF60. Abl binds Cdo and JLP and promotes p38 activation and myogenesis. Activated MKK6 rescues the defective differentiation program caused by loss of Cdo, Bnip-2, or Abl, but the role of endogenous MKK6 (or MKK3) has not been established, so a question mark accompanies its position.