ASSOCIATION OF PROTEIN-KINASES ERK1 AND ERK2 WITH P75 NERVE GROWTH-FACTOR RECEPTORS

Extracellular signal-regulated protein kinases (ERKs) constitute a fam ily of protein serine-threonine kinases implicated in a variety of cel l-signaling pathways. In cultured rat pheochromocytoma PC12 cells, ERK 1 and ERK2 are activated by nerve growth factor (NGF), which also indu ces rapid association between ERK1 and the high affinity gp140prototrk tyrosine kinase NGF receptor. In the present work, we investigated th e possible association between ERKs and the low affinity NGF receptor, p75. Extracts of PC 12 cells (before and after NGF treatment) were su bjected to immunoprecipitation with anti-p75 antibodies or antiserum; the immune complexes were then assessed for the presence of ERK protei ns and tyrosine phosphorylation or for ERK activity using a specific s ubstrate peptide. ERK1 and, to a lesser extent, ERK2 were found to be constitutively associated with p75. NGF did not modulate the total amo unt of ERK proteins co-immunoprecipitated with p75 but did markedly st imulate the level of p75-associated ERK catalytic activity. NGF treatm ent also enhanced the tyrosine phosphorylation of a p75-associated spe cies that co-migrates with ERK1 in Western blots. Finally, K-252a, a c ompound that specifically inhibits activation by NGF of gp140prototrk, abolished the latter effect. These findings indicate that NGF, via ac tivation of gp140prototrk, leads to association of enzymatically activ e ERKs with p75 and raise the possibility that this interaction may pl ay a role in the NGF mechanism of action.