Structure and function of phosphatidylinositol 3-kinase: a potential second messenger system involved in growth control.
Ligand stimulation of growth factor receptors with intrinsic protein-tyrosine kinase activity initiates the assembly of multienzyme signalling complexes. This is mediated by binding of proteins with src homology 2 (SH2) domains to receptor autophosphorylation sites. Among the proteins involved in complex formation is phosphatidylinositol (PI) 3-kinase, a heterodimeric enzyme composed of 85 kDa and 110 kDa subunits, which binds to receptor (and non-receptor) phosphotyrosine residues through the two SH2 domains in the p85 subunit. p85 acts as an adaptor protein and possibly a regulator of the p110 catalytic subunit that phosphorylates phosphoinositides at the D-3 position of the inositol ring. p85 subunit is composed of several distinct functional domains: one SH3 and two SH2 domains, a p110 binding site and a region with homology to BCR. Expression of these domains in E. coli as GST-fusion proteins has allowed definition by nuclear magnetic resonance (NMR) of three-dimensional structures for the SH2 and SH3 domains. The relationship of structure to function for these domains is discussed. The p110 catalytic domain has a region of homology with vps34p of Saccharomyces cerevisiae, a protein involved in protein sorting to the yeast vacuole. Possible clues to the function of PI 3-kinase derived from this and other observations are presented.
Fry
M J
MJ
Ludwig Institute for Cancer Research, London, U.K.
Waterfield
M D
MD
D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000201:enzymology; D002417:Cattle; D015870:Gene Expression; D006128:Growth / Q000502:physiology; D046911:Macromolecular Substances; D008954:Models, Biological; D008969:Molecular Sequence Data; D019869:Phosphatidylinositol 3-Kinases; D010770:Phosphotransferases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism; D015290:Second Messenger Systems; D017386:Sequence Homology, Amino Acid
D046911:Macromolecular Substances; D011956:Receptors, Cell Surface; D010770:Phosphotransferases; D019869:Phosphatidylinositol 3-Kinases