Identification and characterization of a new oncogene derived from the regulatory subunit of phosphoinositide 3‐kinase

p85/p110 phosphoinositide 3‐kinase (PI3K) is a heterodimer composed of a p85‐regulatory and a p110‐catalytic subunit, which is involved in a variety of cellular responses including cytoskeletal organization, cell survival and proliferation. We describe here the cloning and characterization of p65‐PI3K, a mutant of the regulatory subunit of PI3K, which includes the initial 571 residues of the wild type p85α‐protein linked to a region conserved in the eph tyrosine kinase receptor family. We demonstrate that this mutation, obtained from a transformed cell, unlike previously engineered mutations of the regulatory subunit, induces the constitutive activation of PI3K and contributes to cellular transformation. This report links the PI3K enzyme to mammalian tumor development for the first time.

[1]  Jonathan A. Cooper,et al.  p110δ, a Novel Phosphatidylinositol 3-Kinase Catalytic Subunit That Associates with p85 and Is Expressed Predominantly in Leukocytes* , 1997, The Journal of Biological Chemistry.

[2]  P. Warne,et al.  Role of Phosphoinositide 3-OH Kinase in Cell Transformation and Control of the Actin Cytoskeleton by Ras , 1997, Cell.

[3]  C. Martínez-A,et al.  Lck is necessary and sufficient for Fas-ligand expression and apoptotic cell death in mature cycling T cells. , 1997, Journal of immunology.

[4]  M. Zvelebil,et al.  p110δ, a novel phosphoinositide 3-kinase in leukocytes , 1997 .

[5]  P. Cohen,et al.  Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Bα , 1997, Current Biology.

[6]  Y. Yazaki,et al.  p85α Gene Generates Three Isoforms of Regulatory Subunit for Phosphatidylinositol 3-Kinase (PI 3-Kinase), p50α, p55α, and p85α, with Different PI 3-Kinase Activity Elevating Responses to Insulin* , 1997, The Journal of Biological Chemistry.

[7]  N. Hay,et al.  The PI 3-kinase/Akt signaling pathway delivers an anti-apoptotic signal. , 1997, Genes & development.

[8]  J. Backer,et al.  Specific activation of p85-p110 phosphatidylinositol 3'-kinase stimulates DNA synthesis by ras- and p70 S6 kinase-dependent pathways , 1997, Molecular and cellular biology.

[9]  D. Pot,et al.  A specific product of phosphatidylinositol 3-kinase directly activates the protein kinase Akt through its pleckstrin homology domain , 1997, Molecular and cellular biology.

[10]  E. Hafen,et al.  The Drosophila phosphoinositide 3‐kinase Dp110 promotes cell growth. , 1996, The EMBO journal.

[11]  L. Cantley,et al.  Structural Organization and Alternative Splicing of the Murine Phosphoinositide 3-Kinase p85α Gene , 1996 .

[12]  G. Cooper,et al.  Growth factor-dependent survival of rodent fibroblasts requires phosphatidylinositol 3-kinase but is independent of pp70S6K activity. , 1996, Oncogene.

[13]  J. Downward,et al.  Activation of phosphoinositide 3‐kinase by interaction with Ras and by point mutation. , 1996, The EMBO journal.

[14]  C. Kahn,et al.  Insulin receptor substrate 1 binds two novel splice variants of the regulatory subunit of phosphatidylinositol 3-kinase in muscle and brain , 1996, Molecular and cellular biology.

[15]  Y. Yazaki,et al.  A Novel 55-kDa Regulatory Subunit for Phosphatidylinositol 3-Kinase Structurally Similar to p55PIK Is Generated by Alternative Splicing of the p85 Gene (*) , 1996, The Journal of Biological Chemistry.

[16]  M. Zvelebil,et al.  Structural and functional diversity of phosphoinositide 3-kinases. , 1996, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[17]  P. Majerus,et al.  The 145-kDa protein induced to associate with Shc by multiple cytokines is an inositol tetraphosphate and phosphatidylinositol 3,4,5-triphosphate 5-phosphatase. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[18]  L. Cantley,et al.  Phosphatidylinositol (3,4,5)P3 interacts with SH2 domains and modulates PI 3-kinase association with tyrosine-phosphorylated proteins , 1995, Cell.

[19]  M. Waterfield,et al.  A family of phosphoinositide 3-kinases in Drosophila identifies a new mediator of signal transduction , 1995, Current Biology.

[20]  T. Hunter,et al.  When is a lipid kinase not a lipid kinase? When it is a protein kinase , 1995, Cell.

[21]  B. Burgering,et al.  Protein kinase B (c-Akt) in phosphatidylinositol-3-OH kinase signal transduction , 1995, Nature.

[22]  M. White,et al.  The structure and function of p55PIK reveal a new regulatory subunit for phosphatidylinositol 3-kinase , 1995, Molecular and cellular biology.

[23]  T. Roberts,et al.  Role of the autophosphorylation site on the biological function of pp56lck. , 1995, Oncogene.

[24]  Andrius Kazlauskas,et al.  The protein kinase encoded by the Akt proto-oncogene is a target of the PDGF-activated phosphatidylinositol 3-kinase , 1995, Cell.

[25]  C. Nobes,et al.  Rho, Rac, and Cdc42 GTPases regulate the assembly of multimolecular focal complexes associated with actin stress fibers, lamellipodia, and filopodia , 1995, Cell.

[26]  P. Hawkins,et al.  PDGF stimulates an increase in GTP–Rac via activation of phosphoinositide 3-kinase , 1995, Current Biology.

[27]  F. Alt,et al.  Defective DNA-dependent protein kinase activity is linked to V(D)J recombination and DNA repair defects associated with the murine scid mutation , 1995, Cell.

[28]  R. Lindberg,et al.  cDNA cloning and tissue distribution of five human EPH-like receptor protein-tyrosine kinases. , 1995, Oncogene.

[29]  A. Toker,et al.  Activation of protein kinase C family members by the novel polyphosphoinositides PtdIns-3,4-P2 and PtdIns-3,4,5-P3. , 1994, The Journal of biological chemistry.

[30]  M. Czech,et al.  Regulation by insulin of phosphatidylinositol 3'-kinase bound to alpha- and beta-isoforms of p85 regulatory subunit. , 1994, The Journal of biological chemistry.

[31]  M. Koegl,et al.  The phosphatidylinositol 3-kinase alpha is required for DNA synthesis induced by some, but not all, growth factors. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[32]  Peter J. Parker,et al.  The activation of phosphatidylinositol 3-kinase by Ras , 1994, Current Biology.

[33]  Andrius Kazlauskas,et al.  PDGF- and insulin-dependent pp70S6k activation mediated by phosphatidylinositol-3-OH kinase , 1994, Nature.

[34]  M. Kasuga,et al.  Activation of phosphoinositide 3-kinase is required for PDGF-stimulated membrane ruffling , 1994, Current Biology.

[35]  M. Hirano,et al.  The interaction of small domains between the subunits of phosphatidylinositol 3-kinase determines enzyme activity. , 1994, Molecular and cellular biology.

[36]  J. Cambier,et al.  Activation of phosphatidylinositol-3' kinase by Src-family kinase SH3 binding to the p85 subunit. , 1994, Science.

[37]  M. Kasuga,et al.  PI 3‐kinase: structural and functional analysis of intersubunit interactions. , 1994, The EMBO journal.

[38]  L. Olson,et al.  Phosphatidylinositol 3-kinase activation is mediated by high-affinity interactions between distinct domains within the p110 and p85 subunits , 1994, Molecular and cellular biology.

[39]  J. Schlessinger,et al.  Cloning of a novel, ubiquitously expressed human phosphatidylinositol 3-kinase and identification of its binding site on p85 , 1993, Molecular and cellular biology.

[40]  P. Hawkins,et al.  Agonist-stimulated synthesis of phosphatidylinositol(3,4,5)-trisphosphate: a new intracellular signalling system? , 1993, Biochimica et biophysica acta.

[41]  J. Pessin,et al.  Phosphatidylinositol 3-kinase functions upstream of Ras and Raf in mediating insulin stimulation of c-fos transcription. , 1993, The Journal of biological chemistry.

[42]  I. Gout,et al.  Divergent regulation of phosphatidylinositol 3-kinase P85 alpha and P85 beta isoforms upon T cell activation. , 1993, The Journal of biological chemistry.

[43]  L. Cantley,et al.  A tightly associated serine/threonine protein kinase regulates phosphoinositide 3-kinase activity , 1993, Molecular and cellular biology.

[44]  G. Panayotou,et al.  Phosphatidyl-inositol 3-kinase: a key enzyme in diverse signalling processes. , 1992, Trends in cell biology.

[45]  S. Volinia,et al.  Phosphatidylinositol 3-kinase: Structure and expression of the 110 kd catalytic subunit , 1992, Cell.

[46]  I. Weissman,et al.  Unexpected effects of the severe combined immunodeficiency mutation on murine lymphomagenesis , 1992, The Journal of experimental medicine.

[47]  J. Blenis,et al.  ras mediates nerve growth factor receptor modulation of three signal-transducing protein kinases: MAP kinase, Raf-1, and RSK , 1992, Cell.

[48]  I. Mérida,et al.  IL-2 binding activates a tyrosine-phosphorylated phosphatidylinositol-3-kinase. , 1991, Journal of immunology.

[49]  T. Roberts,et al.  Characterization of an active, non-myristylated, cytoplasmic form of the lymphoid protein tyrosine kinase pp56lck. , 1991, International Immunology.

[50]  V. Fried,et al.  cDNA cloning of a Novel 85 kd protein that has SH2 domains and regulates binding of PI3-kinase to the PDGF β-receptor , 1991, Cell.

[51]  A. Ullrich,et al.  Cloning of PI3 kinase-associated p85 utilizing a novel method for expression/cloning of target proteins for receptor tyrosine kinases , 1991, Cell.

[52]  G. Panayotou,et al.  Characterization of two 85 kd proteins that associate with receptor tyrosine kinases, middle-T/pp60c-src complexes, and PI3-kinase , 1991, Cell.

[53]  L. Cantley,et al.  Polyphosphoinositides produced by phosphatidylinositol 3-kinase are poor substrates for phospholipases C from rat liver and bovine brain. , 1989, The Journal of biological chemistry.

[54]  R. Coffman,et al.  cDNA clones encoding IgE-binding factors from a rat-mouse T-cell hybridoma. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[55]  E. Lund,et al.  Human U1 RNA genes contain an unusually sensitive nuclease S1 cleavage site within the conserved 3' flanking region. , 1984, Proceedings of the National Academy of Sciences of the United States of America.