Phosphatidylinositol (3,4,5)P3 interacts with SH2 domains and modulates PI 3-kinase association with tyrosine-phosphorylated proteins.

Rameh LE, Chen CS, Cantley LC
Cell. 1995 83 (5): 821-30

PMID: 8521499 · DOI:10.1016/0092-8674(95)90195-7

Src homology 2 (SH2) domains on the regulatory subunit of phosphoinositide 3-kinase (PI 3-kinase) mediate its binding to specific tyrosine-phosphorylated proteins in stimulated cells. Using a pharmacological and genetic approach, we show that the amount of PI 3-kinase associated with tyrosine-phosphorylated proteins inversely correlates with the amount of PI 3-kinase lipid products present in the cell. An explanation for this observation is provided by our finding that phosphatidylinositol (3,4,5)trisphosphate (Ptdlns [3,4,5]P3) binds directly and selectively to the SH2 domains of the 85 kDa subunit of PI 3-kinase and thereby blocks binding to tyrosine-phosphorylated proteins. The SH2 domain of pp60C-STC also specifically bound Ptdlns (3,4,5)P3, and the binding was competed by a phosphopeptide specific for the Src SH2 domain. These results indicate that production of Ptdlns (3,4,5)P3 at the membrane disrupts the binding of PI 3-kinase to phosphoproteins. This lipid may also recruit other SH2-containing proteins to the membrane to initiate downstream signaling.

MeSH Terms (22)

Amino Acid Sequence Androstadienes Animals Binding, Competitive CHO Cells Chromones Cricetinae Enzyme Inhibitors Humans Insulin Molecular Sequence Data Morpholines Phosphatidylinositol 3-Kinases Phosphatidylinositol Phosphates Phosphoproteins Phosphotransferases (Alcohol Group Acceptor) Phosphotyrosine Proto-Oncogene Proteins pp60(c-src) Receptor, Insulin src Homology Domains Transfection Wortmannin

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