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Naturally occurring tyrosine kinase inserts block high affinity binding of phospholipase C gamma and Shc to TrkC and neurotrophin-3 signaling.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 1995 Sep 01; Vol. 270 (35), pp. 20384-90. - Publication Year :
- 1995
-
Abstract
- Neurotrophin-3 binds to the receptor tyrosine kinase, TrkC. Several naturally occurring splice variants of TrkC exist including those with 14- and 39-amino acid inserts within the tyrosine kinase homology region. When expressed in fibroblasts, full-length TrkC, but not the kinase insert variants, mediated neurotrophin-3-stimulated cell proliferation. We investigated the molecular basis of this signaling defect. The kinase inserts blocked the ability of TrkC to mediate neurotrophin-3 stimulated c-myc and c-fos transcription and activation of the AP-1 transcriptional complex. In cells expressing full-length TrkC, neurotrophin-3 promoted a sustained activation of mitogen-activated protein kinase; TrkC containing kinase inserts only mediated transient activation of mitogen-activated protein kinase. The kinase inserts specifically blocked neurotrophin-3-stimulated autophosphorylation of the phospholipase C gamma binding site on TrkC (tyrosine 789) resulting in a severe reduction in phospholipase C gamma association with TrkC and its tyrosine phosphorylation. Neurotrophin-3-stimulated phosphorylation of the Shc binding site (tyrosine 485) on TrkC, and tyrosine phosphorylation of Shc itself, was unaffected by the kinase inserts; however, the kinase inserts blocked high affinity Shc association with TrkC. It is proposed that the lack of high affinity binding of Shc and/or phospholipase C gamma to the TrkC kinase insert variants may be responsible for the inability of these variants to bring about a full biological response in fibroblasts.
- Subjects :
- 3T3 Cells
Amino Acid Sequence
Animals
Base Sequence
Binding Sites
Cell Division drug effects
DNA Primers
Enzyme Activation drug effects
Fibroblasts cytology
Fibroblasts drug effects
Fibroblasts metabolism
Isoenzymes metabolism
Kinetics
Mice
Molecular Sequence Data
Mutagenesis, Insertional
Neurotrophin 3
Phosphorylation
Receptor, Ciliary Neurotrophic Factor
Receptor, trkC
Receptors, Nerve Growth Factor isolation & purification
Recombinant Proteins metabolism
Substrate Specificity
Transfection
Calcium-Calmodulin-Dependent Protein Kinases metabolism
Nerve Growth Factors pharmacology
Protein-Tyrosine Kinases metabolism
Receptor Protein-Tyrosine Kinases metabolism
Receptors, Nerve Growth Factor metabolism
Signal Transduction
Type C Phospholipases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0021-9258
- Volume :
- 270
- Issue :
- 35
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 7657612
- Full Text :
- https://doi.org/10.1074/jbc.270.35.20384