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

Cell. 1995 Dec 1;83(5):821-30. 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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

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


  • Androstadienes
  • Chromones
  • Enzyme Inhibitors
  • Insulin
  • Morpholines
  • Phosphatidylinositol Phosphates
  • Phosphoproteins
  • phosphatidylinositol 3,4,5-triphosphate
  • Phosphotyrosine
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Phosphatidylinositol 3-Kinases
  • Phosphotransferases (Alcohol Group Acceptor)
  • Receptor, Insulin
  • Proto-Oncogene Proteins pp60(c-src)
  • Wortmannin