Nerve growth factor stimulates the tyrosine phosphorylation of a 38-kDa protein that specifically associates with the src homology domain of phospholipase C-gamma 1.
The cellular actions of nerve growth factor (NGF) involve changes in protein phosphorylation, initiated by the binding and subsequent activation of its tyrosine kinase receptor, the trk protooncogene (pp140c-trk). Upon exposure to NGF, a 38-kDa tyrosine-phosphorylated protein (pp38) is identified in both PC-12 pheochromocytoma cells and NIH3T3 cells transfected with ... the full-length human pp140c-trk cDNA (3T3-c-trk) that is specifically coimmunoprecipitated with pp140c-trk or phosphatidylinositol-phospholipase C (PLC)-gamma 1. In both PC-12 and 3T3-c-trk cells, NGF rapidly stimulates the association of pp140c-trk and pp38 with a fusion protein containing the src homology (SH) domains of PLC gamma 1. This phosphorylation and subsequent association are specific for NGF, since epidermal growth factor, platelet-derived growth factor, and insulin do not stimulate the tyrosine phosphorylation of these proteins or their association with the PLC gamma 1 SH domains, although the receptors for these growth factors do undergo tyrosine phosphorylation and association with the PLC-gamma 1 fusion protein under these conditions. Furthermore, the NGF-dependent pp38-SH binding is specific for the SH2 domains of PLC-gamma 1, since the phosphoprotein does not bind to fusion proteins containing SH domains of ras GTPase-activating protein or the p85 subunit of phosphatidylinositol 3 kinase. Both amino- and carboxyl-terminal SH2 domains of PLC-gamma 1 are necessary for the association of pp38 with PLC-gamma 1, although each SH2 domain is sufficient for the association of pp140c-trk with PLC-gamma 1. In both PC-12 and 3T3-c-trk cells, the phosphorylation and association of pp38 with PLC gamma 1 is rapid, occurring maximally at 1 min and declining thereafter. Moreover, this effect of NGF is dose-dependent over a physiological concentration of the growth factor. The specificity and rapidity of pp38 phosphorylation and its association with PLC-gamma 1 suggest that it may be an important component in signal transduction for NGF.
Mesh Terms:
3T3 Cells, Animals, Blotting, Western, DNA, Electrophoresis, Polyacrylamide Gel, GTPase-Activating Proteins, Genes, src, Isoenzymes, Kinetics, Mice, Nerve Growth Factors, PC12 Cells, Phosphorylation, Protein-Tyrosine Kinases, Proteins, Proto-Oncogene Proteins, Receptor, trkA, Receptors, Nerve Growth Factor, Type C Phospholipases, Tyrosine, ras GTPase-Activating Proteins
3T3 Cells, Animals, Blotting, Western, DNA, Electrophoresis, Polyacrylamide Gel, GTPase-Activating Proteins, Genes, src, Isoenzymes, Kinetics, Mice, Nerve Growth Factors, PC12 Cells, Phosphorylation, Protein-Tyrosine Kinases, Proteins, Proto-Oncogene Proteins, Receptor, trkA, Receptors, Nerve Growth Factor, Type C Phospholipases, Tyrosine, ras GTPase-Activating Proteins
J. Biol. Chem.
Date: Oct. 25, 1992
PubMed ID: 1400471
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