The TrkB receptor tyrosine kinase regulates cellular proliferation via signal transduction pathways involving SHC, PLCgamma, and CBL

J Recept Signal Transduct Res. 1999 Nov;19(6):953-74. doi: 10.3109/10799899909038434.

Abstract

The TrkB protein tyrosine kinase is a high affinity receptor for brain derived neurotrophic factor (BDNF) and neurotrophin-4 (NT-4). TrkB autophosphorylation occurs on five cytoplasmic tyrosines: Y484, Y670, Y674, Y675, and Y785. Using site directed mutagenesis, we have assessed the importance of TrkB tyrosines 484 and 785 in affecting TrkB-mediated signaling events leading to NIH 3T3 cell mitogenesis and survival. Mutation of TrkB tyrosine 484, while having no affect on BDNF-inducible PLCgamma and Cbl tyrosine phosphorylation, is essential for the phosphorylation of Shc, the complete activation of extracellular regulated kinase 1/2 (ERK1/2) and the induction of c-fos protein synthesis. In contrast, mutation of Y785 does not significantly affect BDNF-inducible Shc phosphorylation, ERK1/2 activation, or c-fos protein synthesis, but completely inhibits the tyrosine phosphorylation of PLCgamma and Cbl. These data indicate that both ERK-dependent and ERK-independent signaling pathways lead to BDNF-inducible mitogenesis and survival.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 3T3 Cells
  • Animals
  • Brain-Derived Neurotrophic Factor / physiology
  • Cell Division / physiology
  • Intramolecular Transferases / physiology*
  • Isoenzymes / physiology*
  • Mice
  • Mutagenesis, Site-Directed
  • Nerve Growth Factors / physiology
  • Oncogene Protein v-cbl
  • Phospholipase C gamma
  • Phosphorylation
  • Rats
  • Receptor, trkB / physiology*
  • Retroviridae Proteins, Oncogenic / physiology*
  • Signal Transduction* / physiology
  • Type C Phospholipases / physiology*

Substances

  • Brain-Derived Neurotrophic Factor
  • Isoenzymes
  • Nerve Growth Factors
  • Oncogene Protein v-cbl
  • Retroviridae Proteins, Oncogenic
  • Receptor, trkB
  • Type C Phospholipases
  • Phospholipase C gamma
  • Intramolecular Transferases
  • squalene-hopene cyclase
  • neurotrophin 4