Identification and characterization of novel substrates of TrK receptors in developing neurons

Neurotrophins influence growth and survival of specific populations of neur ons through activation of Trks, members of the receptor tyrosine kinase (RT K) family. In this report, we describe the identification and characterizat ion of two substrates of Trk kinases, rAPS and SH2-B, which are closely rel ated Src homolog 2 (SH2) domain-containing signaling molecules, rAPS and SH 2-B are substrates of TrkB and TrkC in cortical neurons and SH2-B is a subs trate of TrkA in sympathetic neurons. Moreover, rAPS and SH2-B bind to Grb2 , and both are sufficient to mediate NGF induction of Pas, MAP kinase (MAPK ), and morphological differentiation of PC12 cells. Lastly, antibody pertur bation and transient transfection experiments indicate that SH2-B, or a clo sely related molecule, is necessary for NGF-dependent signaling in neonatal sympathetic neurons. Together, these observations indicate that rAPS and S H2-B mediate Trk signaling in developing neurons.