SH2-B and APS are multimeric adapters that augment TrkA signaling

Neurotrophins influence growth and survival of sympathetic and sensory neur ons through activation of their receptors, Trk receptor tyrosine kinases. P reviously, we identified Src homology 2-B (SH2-B) and APS, which are struct urally similar adapter proteins, as substrates of Trk kinases, In the prese nt study, we demonstrate that both SH2-B and APS exist in cells as homopent amers and/or heteropentamers, independent of Trk receptor activation. Struc ture-function analyses revealed that the SH2-B multimerization domain resid es within its amino terminus, which is necessary for SH2-B-mediated nerve g rowth factor (NGF) signaling. Overexpression of SH2-B enhances both the mag nitude and duration of TrkA autophosphorylation following exposure of PC12 cells to NGF, and this effect requires the amino-terminal multimerization m otif, Moreover, the amino terminus of SH2-B is necessary for TrkA/SH2-B-med iated morphological differentiation of PC12 cells. Together, these results indicate that the multimeric adapters SH2-B and APS influence neurotrophin signaling through direct modulation of Trk receptor autophosphorylation.