Negative regulation of PI 3-kinase by Ruk, a novel adaptor protein.
Class I(A) phosphatidylinositol 3-kinase ( PI 3-kinase) is a key component of important intracellular signalling cascades. We have identified an adaptor protein, Ruk(l), 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(l) substantially inhibits the lipid kinase activity of the enzyme. Overexpression of Ruk(l) in cultured primary neurons induces apoptosis, an effect that could be reversed by co-expression of constitutively activated forms of the p110 alpha 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.[1]References
- Negative regulation of PI 3-kinase by Ruk, a novel adaptor protein. Gout, I., Middleton, G., Adu, J., Ninkina, N.N., Drobot, L.B., Filonenko, V., Matsuka, G., Davies, A.M., Waterfield, M., Buchman, V.L. EMBO J. (2000) [Pubmed]
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