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

Class I-A phosphatidylinositol 3-kinase (PI3-kinase) is a key component of important intracellular signalling cascades. We have identified an adaptor protein, Ruk(1), 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 p85 alpha regulatory subunit of the class I-A PI 3-kinase. In contrast to many other adaptor proteins that activate PI 3-kinase, interaction with Ruk(1) substantially inhibits the lipid kinase activity of the enzyme. Overexpression of Ruk(1) in cultured primary neurons induces apoptosis, an effect that could be reversed by co-expression of constitutively activated forms of the p110 alpha a 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.