REGULATION OF THE TYROSINE KINASE SUBSTRATE EPS8 EXPRESSION BY GROWTH-FACTORS, V-SRC AND TERMINAL DIFFERENTIATION

SH3-containing proteins are involved in signal transduction by a numbe r of growth factor receptors and in the organization of the cytoskelet on. The recently identified Eps8 protein, which contains an SH3 domain , is coupled functionally and physically to the EGFR and is tyrosine p hosphorylated by this receptor and other receptors as well,Here, we ex amined the regulation of eps8 expression in response to mitogenic or d ifferentiative signals, We show that Eps8 is expressed at low levels i n resting fibroblasts, but its expression is strongly induced during a ctivation by serum, phorbol esters and the v-src oncogene, Conversely, expression of Eps8, but not of other EGFR substrates such as She or E ps15, is virtually extinguished in non-proliferating, terminally diffe rentiated murine myogenic cells, The putative role of Eps8 protein as a v-Src substrate was analysed in murine fibroblasts and in quail myog enic cells expressing a temperature-sensitive variant of the tyrosine kinase, Tyrosine phosphorylation of Eps8 was detected only at the perm issive temperature, A non-myristylated, transformation-defective mutan t of v-Src did not phosphorylate Eps8, whereas it phosphorylated She. Together, these findings indicate that Eps8 may be a critical substrat e of v-Src, They further establish Eps8 as an example of a signal tran sducer whose expression senses the balance between growth and differen tiation and might, therefore, be involved in the determination of the phenotype.