Journal
EMBO JOURNAL
Volume 19, Issue 15, Pages 4015-4025Publisher
WILEY
DOI: 10.1093/emboj/19.15.4015
Keywords
adaptor protein; neuronal apoptosis; phosphoinositide 3-kinase; signal transduction
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Funding
- NCI NIH HHS [CA21765] Funding Source: Medline
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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.
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