Structure and function of phosphoinositide 3-kinases

Phosphoinositide kinases (PI3Ks) play an important role in mitogenic signal ing and cell survival, cytoskeletal remodeling, metabolic control and vesic ular trafficking. Here we summarize the structure-function relationships de lineating the activation process of class I PI3Ks involving various domains of adapter subunits, Ras, and interacting proteins. The resulting product, PtdIns(3,4,5)P-3, targets Akt/protein kinase B (PKB), Bruton's tyrosine ki nase (Btk), phosphoinositide-dependent kinases (PDK), integrin-linked kinas e (ILK), atypical protein kinases C (PKC), phospholipase C gamma and more. Surface receptor-activated PI3Ks function in mammals, insects, nematodes an d slime mold, but not yeast. While many members of the class II family have been identified and characterized biochemically, it is presently unknown h ow these C2-domain containing PI3Ks are activated, and which PI substrate t hey phosphorylate in vivo. PtdIns 3-P is produced by Vps34p/class III PI3Ks and operates via the PtdIns 3-P-binding proteins early endosomal antigen ( EEA1), yeast Vac1p, Vps27p, Pip1p in lysosomal protein targeting. Besides t he production of D3 phosphorylated lipids, PI3Ks have an intrinsic protein kinase activity. For trimeric GTP-binding protein-activated PI3K gamma, pro tein kinase activity seems to be sufficient to trigger mitogen-activated pr otein kinase (MAPK). Recent disruption of PI3K genes in slime mold, Caenorh abditis elegans, Drosophila melanogaster and mice further underlines the im portance of PI3K signaling systems and elucidates the role of PI3K signalin g in multicellular organisms. (C) 1998 Elsevier Science B.V. All rights res erved.