TRANSIENT ASSOCIATION OF THE PHOSPHOTYROSINE PHOSPHATASE SHP-2 WITH TRK4 IS INDUCED BY NERVE GROWTH-FACTOR

Nerve growth factor (NGF) treatment of rat PC12 pheochromocytoma cells results in an increase in the tyrosine phosphorylation of the NGF rec eptor, TrkA, leading to differentiation to a neuronal phenotype, Depho sphorylation by protein tyrosine phosphatases (PTPases) is thought to play an important Pole in regulating this signaling pathway, To identi fy PTPases that are recruited to the activated TrkA receptor, we used an ingel PTPase assay to examine the presence of PTPases in TrkA immun oprecipitates. The Src homology 2 domain containing PTPase SHP-2 was f ound to associate transiently with TrkA following receptor activation, reaching a peak after 1 min of NGF treatment and then decreasing rapi dly. The association of SHP-2 with TrkA was accompanied by the tyrosin e phosphorylation of SHP-2 and an association of SHP-2 with multiple t yrosine-phosphorylated proteins. In addition, the PTPase activity in S HP-2 immunoprecipitates increased greater than twofold after I min of NGF treatment. This is the first demonstration that the association of SHP-2 with TrkA is induced by NGF and that this association leads to SHP-2 activation and tyrosine phosphorylation. We conclude that SHP-2 plays a significant role in early biochemical events in TrkA-mediated signal transduction.