Negative regulation of PI 3-kinase by Ruk, a novel adaptor protein.

Class IA phosphatidylinositol 3-kinase (PI 3-kinase) is a key component of important intracellular signalling cascades. We have identified an adaptor protein, Rukl, which forms complexes with the PI 3-kinase holoenzyme in vitro and in vivo. This interaction involves the proline-rich region of Ruk and the SH3 domain of the p85α regulatory subunit of the class IA PI 3-kinase. In contrast to many other adaptor proteins that activate PI 3-kinase, interaction with Rukl substantially inhibits the lipid kinase activity of the enzyme. Overexpression of Rukl in cultured primary neurons induces apoptosis, an effect that could be reversed by co-expression of constitutively activated forms of the p110α catalytic subunit of PI 3-kinase or its downstream effector PKB/Akt. Our data provide evidence for the existence of a negative regulator of the PI 3-kinase signalling pathway that is essential for maintaining cellular homeostasis. Structural similarities between Ruk, CIN85 and CD2AP/CMS suggest that these proteins form a novel family of adaptor molecules that are involved in various intracellular signalling pathways.