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

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Abstract
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.