A ROLE FOR SAM68 IN CELL-CYCLE PROGRESSION ANTAGONIZED BY A SPLICED VARIANT WITHIN THE KH DOMAIN

Sam68 is the main tyrosine-phosphorylated and Src-associated protein i n mitotic cells. Sam68 exhibits a conserved functional KH (hnRNPK homo logy) RNA binding domain and binds single strand nucleic acids. Tyrosi ne phosphorylation mediates the interaction of Sam68 with many SH3- an d SH2-containing proteins and negatively regulates its nucleic acid bi nding properties. But the function and the impact of Sam68 on cell sig naling and cell proliferation remains elusive. We report here the iden tification of a natural isoform of Sam68 with a deletion within the KH domain. This isoform, called Sam68 Delta KH, is specifically expresse d at growth arrest upon confluency in normal cells. In cells that do n ot enter quiescence at confluency such as Src-transformed cells, no re cruitment of Sam68 Delta KH is observed. Transfected Sam68 Delta KH in hibits serum-induced DNA synthesis and cyclin D1 expression. Sam68 ove rcomes these effects, suggesting that isoforms of Sam68 are involved, through KH domain signaling, in cell proliferation, and more precisely in G(1)/S transition.