The TRKB receptor tyrosine kinase regulates cellular proliferation via signal transduction pathways involving SHC, PLC gamma, and CBL

The TrkB protein tyrosine kinase is a high affinity receptor for brain deri ved neurotrophic factor (BDNF) and neurotrophin-4 (NT-4). TrkB autophosphor ylation occurs on five cytoplasmic tyrosines: Y484, Y670, Y674, Y675, and Y 785. Using site directed mutagenesis, we have assessed the importance of Tr kB tyrosines 484 and 785 in affecting TrkB-mediated signaling events leadin g to NIH 3T3 cell mitogenesis and survival. Mutation of TrkB tyrosine 484, while having no affect on BDNF-inducible PLC gamma and Cbl tyrosine phospho rylation, is essential for the phosphorylation of Shc, the complete activat ion of extracellular regulated kinase 1/2 (ERK1/2) and the induction of c-f os protein synthesis. In contrast, mutation of Y785 does not significantly affect BDNF-inducible She phosphorylation, ERK1/2 activation, or c-fos prot ein synthesis, but completely inhibits the tyrosine phosphorylation of PLC gamma and Cbl. These data indicate that both ERK-dependent and ERK-independ ent signaling pathways lead to BDNF-inducible mitogenesis and survival.