Cdc42 stimulates RNA splicing via the S6 kinase and a novel S6 kinase target, the nuclear cap-binding complex

Cdc42 is a low molecular weight GTP-binding protein that plays a key regula tory role in a variety of cellular activities. The importance of the coordi nation of different cell functions by Cdc42 is underscored by the fact that a constitutively active Cdc42 mutant induces cellular transformation. In t his study, we describe a novel function for Cdc42: its ability to stimulate pre-messenger RNA splicing. This activity is dependent on cysteine 37 in t he effector loop of Cdc42 but is not dependent on cell growth. A likely can didate protein for mediating the Cdc42 effects on pre-mRNA splicing is the nuclear RNA cap-binding complex (CBC), which plays a key role in an early s tep of cap dependent RNA splicing. Activation of the CBC by Cdc42 can be in hibited by rapamycin, Additionally, phosphatidylinositol 3-kinase and the C dc42 effector, pp70 Se kinase, stimulate the RNA cap-binding activity of th e CBC, S6 kinase may directly target the CBC in vivo as it can phosphorylat e the 80-kDa subunit of the CBC, CBP80, at residues that are subject to a g rowth factor-dependent and rapamycin-sensitive phosphorylation in vivo. Tog ether these data suggest the involvement of a Cdc42-S6 kinase pathway in th e regulation of RNA splicing, mediated by an increase in capped RNA binding by the CBC, as well as raise the possibility that the effects of Cdc42 on cell growth may be due in part to its regulation of RNA processing.