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.
Mesh Terms:
1-Phosphatidylinositol 3-Kinase, Amino Acid Sequence, Animals, Apoptosis, Binding Sites, Cloning, Molecular, DNA, Complementary, Gene Expression Regulation, Enzymologic, Humans, Mice, Molecular Sequence Data, Neoplasm Proteins, Nerve Tissue Proteins, Neurons, Afferent, Protein Binding, Protein Isoforms, Recombinant Proteins, Sequence Analysis, DNA, Sequence Homology, Amino Acid, Signal Transduction, U937 Cells, src Homology Domains
EMBO J.
Date: Aug. 01, 2000
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