The TrkB receptor tyrosine kinase regulates cellular proliferation via signal transduction pathways involving SHC, PLCgamma, and CBL.
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.
McCarty
J H
JH
Department of Molecular, Cellular and Developmental Biology and Neuroscience Research Institute, University of California, Santa Barbara 93106, USA.
Feinstein
S C
SC
D016475:3T3 Cells; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D019751:Intramolecular Transferases / Q000502:physiology*; D007527:Isoenzymes / Q000502:physiology*; D051379:Mice; D016297:Mutagenesis, Site-Directed; D009414:Nerve Growth Factors / Q000502:physiology; D050722:Oncogene Protein v-cbl; D051966:Phospholipase C gamma; D010766:Phosphorylation; D051381:Rats; D020813:Receptor, trkB / Q000502:physiology*; D015682:Retroviridae Proteins, Oncogenic / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D010738:Type C Phospholipases / Q000502:physiology*
D019208:Brain-Derived Neurotrophic Factor; D007527:Isoenzymes; D009414:Nerve Growth Factors; D050722:Oncogene Protein v-cbl; D015682:Retroviridae Proteins, Oncogenic; D020813:Receptor, trkB; D010738:Type C Phospholipases; D051966:Phospholipase C gamma; D019751:Intramolecular Transferases; C066630:squalene-hopene cyclase; C073922:neurotrophin 4