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The retroviral oncogene p3k(v-p3k) of avian sarcoma virus 16 (ASV16) codes for the catalytic subunit of phosphoinositide (PI) 3-kinase, p110α. The v-P3k protein is oncogenic in vivo and in vitro; its cellular counterpart, c-P3k, lacks oncogenicity. Fusion of viral Gag sequences to the amino terminus of c-P3k activates the transforming potential. Activation can also be achieved by the addition of a myristylation signal to the amino terminus or of a farnesylation signal to the carboxyl terminus of c-P3k. A mutated myristylation signal was equally effective; it also caused a strong increase in the kinase activity of P3k. Mutations that inactivate lipid kinase activity abolish oncogenicity. The transforming activity of P3k is correlated with the ability to induce activating phosphorylation in Akt. Point mutations and amino-terminal deletions recorded in v-P3k were shown to be irrelevant to the activation of oncogenic potential. Interactions of P3k with the regulatory subunit of PI 3-kinase, p85, or with Ras are not required for transformation. These results support the conclusion that the oncogenicity of P3k depends on constitutive lipid kinase activity. Akt is an important and probably essential downstream component of the oncogenic signal from P3k. The retroviral oncogene p3k(v-p3k) of avian sarcoma virus 16 (ASV16) codes for the catalytic subunit of phosphoinositide (PI) 3-kinase, p110α. The v-P3k protein is oncogenic in vivo and in vitro; its cellular counterpart, c-P3k, lacks oncogenicity. Fusion of viral Gag sequences to the amino terminus of c-P3k activates the transforming potential. Activation can also be achieved by the addition of a myristylation signal to the amino terminus or of a farnesylation signal to the carboxyl terminus of c-P3k. A mutated myristylation signal was equally effective; it also caused a strong increase in the kinase activity of P3k. Mutations that inactivate lipid kinase activity abolish oncogenicity. The transforming activity of P3k is correlated with the ability to induce activating phosphorylation in Akt. Point mutations and amino-terminal deletions recorded in v-P3k were shown to be irrelevant to the activation of oncogenic potential. Interactions of P3k with the regulatory subunit of PI 3-kinase, p85, or with Ras are not required for transformation. These results support the conclusion that the oncogenicity of P3k depends on constitutive lipid kinase activity. Akt is an important and probably essential downstream component of the oncogenic signal from P3k. phosphoinositide avian sarcoma virus 16 chicken embryo fibroblasts platelet-derived growth factor polyacrylamide gel electrophoresis avian sarcoma virus 8905 phosphate-buffered saline polymerase chain reaction PI1 3-kinases of class IA consist of a catalytic subunit p110 and a regulatory subunit p85. P110 can bind to p85 and is controlled by p85. These lipid kinases affect many biological functions such as cell proliferation, differentiation, apoptosis, and glucose transport (1.Zvelebil M.J. Macdougall L. Leevers S. Volinia S. Vanhaesebroeck B. Gout I. Panayotou G. Domin J. Stein R. Pages F. Koga H. Salim K. Linacre J. Das P. Panaretou C. Wetzker R. Waterfield M. Phil. Trans. R. Soc. Lond. B. 1996; 351: 217-223Crossref PubMed Scopus (89) Google Scholar, 2.Shepherd P.R. Withers D.J. Siddle K. Biochem. J. 1998; 333: 471-490Crossref PubMed Scopus (841) Google Scholar, 3.Wymann M.P. Pirola L. Biochim. Biophys. Acta. 1998; 1436: 127-150Crossref PubMed Scopus (580) Google Scholar, 4.Fruman D.A. Meyers R.E. Cantley L.C. Annu. Rev. Biochem. 1998; 67: 481-507Crossref PubMed Scopus (1323) Google Scholar, 5.Alessi D.R. Downes C.P. Biochim. Biophys. Acta. 1998; 1436: 151-164Crossref PubMed Scopus (191) Google Scholar, 6.Carpenter C.L. Cantley L.C. Biochim. Biophys. Acta. 1996; 1288: M11-116PubMed Google Scholar, 7.Vanhaesebroeck B. 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Biol. 1989; 9: 1651-1658Crossref PubMed Scopus (131) Google Scholar). The catalytic subunit p110α can also be activated by a direct interaction with GTP-loaded Ras, another oncoprotein (13.Rodriguez-Viciana P. Warne P.H. Vanhaesebroeck B. Waterfield M.D. Downward J. EMBO J. 1996; 15: 2442-2451Crossref PubMed Scopus (501) Google Scholar, 14.Rodriguez-Viciana P. Warne P.H. Khwaja A. Marte B.M. Pappin D. Das P. Waterfield M.D. Ridley A. Downward J. Cell. 1997; 89: 457-467Abstract Full Text Full Text PDF PubMed Scopus (961) Google Scholar). The isolation of a retroviral oncogene, v-p3k, coding for a homologue of p110α established an active role of PI 3-kinase in oncogenic transformation (15.Chang H.W. Aoki M. Fruman D. Auger K.R. Bellacosa A. Tsichlis P.N. Cantley L.C. Roberts T.M. Vogt P.K. Science. 1997; 276: 1848-1850Crossref PubMed Scopus (391) Google Scholar). v-p3k was cloned from the genome of avian sarcoma virus 16 (ASV16), an agent causing hemangiosarcomas in chickens (15.Chang H.W. Aoki M. Fruman D. Auger K.R. Bellacosa A. Tsichlis P.N. Cantley L.C. Roberts T.M. Vogt P.K. Science. 1997; 276: 1848-1850Crossref PubMed Scopus (391) Google Scholar). The v-P3k protein differs from its cellular counterpart, c-P3k, in two major points. 1) The first 13 amino acids of c-P3k are deleted in v-P3k and replaced by retroviral Gag sequences, and 2) v-P3k carries several amino acid substitutions; they are located outside the kinase domain. Expression of v-P3k induces oncogenic transformation in cultures of chicken embryo fibroblasts (CEF) and hemangiosarcomas in young chickens, suggesting that a constitutively active PI 3-kinase is sufficient for the transformation of chicken cells (15.Chang H.W. Aoki M. Fruman D. Auger K.R. Bellacosa A. Tsichlis P.N. Cantley L.C. Roberts T.M. Vogt P.K. Science. 1997; 276: 1848-1850Crossref PubMed Scopus (391) Google Scholar). Recent findings further support the involvement of PI 3-kinase in development of cancer. These include amplification of PIK3CA, the human counterpart of c-p3k, in human ovarian cancer cell lines (16.Shayesteh L. Lu Y. Kuo W.L. Baldocchi R. Godfrey T. Collins C. Pinkel D. Powell B. Mills G.B. Gray J.W. Nat. Genet. 1999; 21: 99-102Crossref PubMed Scopus (1011) Google Scholar), isolation of an oncogenic mutant of p85 which can transform mammalian fibroblasts in collaboration with the v-rafoncogene (17.Jimenez C. Jones D.R. Rodriguez-Viciana P. Gonzalez-Garcia A. Leonardo E. Wennstrom S. von Kobbe C. Toran J.L., L, R.B. Calvo V. Copin S.G. Albar J.P. Gaspar M.L. Diez E. Marcos M.A. Downward J. Martinez A.C. Merida I. Carrera A.C. 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A. 1999; 96: 4240-4255Crossref PubMed Scopus (1754) Google Scholar). The v-P3k protein is much more potent in inducing oncogenic transformation than the wild type cellular c-P3k. Here we report that this difference in activity is caused by the fusion of v-P3k to viral Gag sequences. We show that membrane localization guided by a myristylation or a farnesylation signal can substitute for Gag in activating the transforming potential. We also describe the isolation of a variant v-p3k gene from a new avian sarcoma virus, ASV8905. An analysis of this variant and of deletion mutants of p110α suggests that oncogenic transformation does not require binding of p110α to the regulatory subunit p85, but is dependent on amino-terminal domains and on lipid kinase activity. CEF cultures were prepared from White Leghorn embryos obtained from SPAFAS (Preston, CT). For focus assays, DNA was transfected into CEF by using the dimethyl S. M. Mol. Cell. Biol. 1984; PubMed Scopus Google Scholar). with virus were as F. T. Vogt P.K. PubMed Scopus Google Scholar). were on or of transformed the were with and were The results shown are from a For cultures were in with and chicken the cells were with platelet-derived growth factor A of CEF was using The was by with and from an avian retroviral DNA of the that was an and was and the was into and The v-p3k 8905 gene was by the amino-terminal of the gene of v-p3k 16 with using in the sequences. The was to the amino terminus and or the carboxyl terminus the of by using a a or a a with sequences for with the amino-terminal sequences amino of with the sequences to were by using and the farnesylation signal of was to the terminus of via using and with a deletion of the first amino and were using a with on the or with on and was by the partially of (15.Chang H.W. Aoki M. Fruman D. Auger K.R. Bellacosa A. Tsichlis P.N. Cantley L.C. Roberts T.M. Vogt P.K. Science. 1997; 276: 1848-1850Crossref PubMed Scopus (391) Google Scholar) the of v-p3k from and a of and were using the with or The deletion mutants of were in the was by using and from the of to was by of by polymerase and was obtained by of by polymerase and is by with The deletion of was by using and deletion mutants of were in the by of by of by polymerase and by of with by polymerase and by of by with by of by polymerase and by of with by polymerase and The sequences of the are as were for in The cells were in A. was to the cell The to protein were with and by gel electrophoresis by were in For of of protein were by and to The were with the was obtained protein kinase and protein kinase were obtained from was obtained from with were by with a to the For of of were with of for and were with protein The were with and by with The were by to the and with as For in lipid kinase assays, the prepared as were with of kinase reaction phosphatidylinositol for The reaction was by of The were with of and the was were in and in a J.P. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). The were to for of CEF was as A. C. Kavanaugh W.M. Apell G. Escobedo M.A. Williams L.T. Mol. Cell. Biol. 1996; PubMed Scopus Google Scholar). CEF were with phosphate-buffered saline and in The was on for and with in a were by for and the was for The was with and as The was in and as on were with and with in for a with cells were with for the were with and with a of for in a with the were with for The were with and on with v-P3k by the retroviral more transformed cell of transfected DNA than c-P3k by the in CEF c-P3k also to as with which virus by the CEF was as in inducing oncogenic transformation as c-P3k a its as an in the retroviral to this of c-P3k, we and of CEF transformed by The c-P3k in this was the carboxyl terminus with a it be from the c-P3k from a focus and were by c-P3k and in the c-P3k protein was than the for c-P3k. of the cell with the Gag protein of the retroviral the and that the c-P3k in was to Gag sequences that in from to of the and that an amino-terminal Gag can the oncogenic of c-P3k. The role of Gag in oncogenic transformation by c-P3k was further by the coding in v-P3k by that of c-P3k thus a was as transforming as of Gag to c-P3k sequences sufficient to oncogenic and the mutations in v-P3k are not essential for transformation in CEF with from from transformed focus from transformed focus from transformed focus from transformed focus from transformed focus transformed focus 16 from avian sarcoma virus 8905 from avian sarcoma virus myristylation signal of the mutated acid from avian sarcoma virus from avian sarcoma virus myristylation signal of the mutated acid in a new CEF that were not for the transformed phenotype much of the c-P3k protein than cultures from transformed cell be the for the of transforming activity with c-P3k. The to c-P3k in in its a of the for the of a a the was to with to the of and the was a was in which c-P3k was amino with a with a of CEF transfected with of P3k to in cells the of transformation for c-P3k and The that the the amino terminus of P3k with transforming activity was addition of a farnesylation signal to the carboxyl terminus of c-P3k in transformation and also These results that of c-P3k are not sufficient for oncogenic of the P3k Cell were by and for P3k with the of transformed cell by P3k CEF were transfected with DNA as was transfected with or of The cells were with for and and with in CEF with of myristylation signal of the farnesylation 8905 from avian sarcoma virus also in and myristylation signal of the farnesylation P3k from avian sarcoma virus ASV8905. in a new also in and Gag sequences can fusion to cell J.W. J. 1996; PubMed Google Scholar), and membrane localization by myristylation or farnesylation shown to PI 3-kinase constitutively active A. C. Kavanaugh W.M. Apell G. Escobedo M.A. Williams L.T. Mol. Cell. Biol. 1996; PubMed Scopus Google B. K. M. Biol. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, B.M. Downward J. Trends Biochem. Sci. 1997; 22: Full Text PDF PubMed Scopus Google Scholar). to for a possible role of membrane localization in oncogenic were with a membrane binding of that a myristylation signal and the amino terminus or a farnesylation signal the carboxyl terminus of c-P3k and were as of the and were transforming in CEF cultures and in focus and are to the that with the with DNA the myristylation the functions as the for and a of this to shown to myristylation A. S. K. J. 64: PubMed Google Scholar). such a to A in the myristylation signal of c-P3k not transforming activity also and in kinase of that and much PI 3-kinase activity than c-P3k or v-P3k of and shown to be These results that c-P3k with a amino terminus kinase activity the acid is The for the of is be to the the lipid kinase activity for the of in cells transfected with c-P3k and v-P3k and The v-P3k transfected cells were by the of the or a that was in c-P3k was found in the but of and were The than of from the a for new a avian sarcoma virus 8905 with an of P3k was A of the protein product of is shown in The amino terminus of the P3k in this genome is to Gag sequences as in but the Gag is of sequences. The fusion also results in a deletion of amino acids from the amino terminus of p110α. 13 amino acids of p110α are deleted the amino-terminal fusion The of p110α in amino acid for the conclusion that amino acid in v-P3k of are not for transformation. The v-P3k of was cloned into and was found to induce oncogenic transformation of CEF and hemangiosarcomas in young chickens and not to for a possible activating role of the amino-terminal deletions in a c-P3k with a acid amino-terminal deletion was and in the transforming activity was and to that of and and addition of a wild type or myristylation signal in strong transforming activity in also and These with the results on and show that the amino-terminal deletions in v-P3k of or are sufficient for oncogenic transformation. the deletion of amino acids from the v-P3k of the of more than of the the interaction of the and the forms of v-P3k with the regulatory subunit p85 was p85 was with P3k from but not with the P3k protein of These show that oncogenic transformation by P3k does not require interaction with the regulatory subunit p85. deletions in domains of P3k were for oncogenic activity. of a myristylation deletions of amino acids and to transform CEF suggesting that the to the is required for oncogenicity. The of this to be of the deletions and a deletion also to induce transformation of CEF suggesting a or role of domains amino acids and and of the carboxyl terminus in the oncogenic activity of P3k. These and deletion mutants were but lipid kinase activity We also the role of Ras binding in P3k transformation. The carries a in the and to with Ras (13.Rodriguez-Viciana P. Warne P.H. Vanhaesebroeck B. Waterfield M.D. Downward J. EMBO J. 1996; 15: 2442-2451Crossref PubMed Scopus (501) Google Scholar) it strong transforming activity in CEF suggests that binding to Ras in not required for transformation by constitutively active PI 3-kinase activity of mutant PI 3-kinase activity was in from of CEF transfected with of mutant Cell were by for P3k with the P3k codes for a lipid kinase that the of the to this kinase activity is for oncogenic two mutations were into is the deletion of the kinase the is a with M.P. G. M.J. Pirola L. Vanhaesebroeck B. Waterfield M.D. Panayotou G. Mol. Cell. 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A. 1998; PubMed Scopus Google activation in CEF P3k Cell were prepared from CEF transfected with of or with were on a gel and to a The was with or The c-P3k protein does not induce oncogenic it is overexpressed with the of sequences. The of transformed cell in cell cultures in (15.Chang H.W. Aoki M. Fruman D. Auger K.R. Bellacosa A. Tsichlis P.N. Cantley L.C. Roberts T.M. Vogt P.K. Science. 1997; 276: 1848-1850Crossref PubMed Scopus (391) Google Scholar) and in the oncogenic of the amino terminus of the c-P3k is to Gag sequences of the retroviral The fusion to Gag sequences retroviral activates the oncogenic of c-P3k. the Gag sequences of v-P3k are to c-P3k in the protein also The amino acid found in the coding of v-P3k are irrelevant for oncogenicity. The two forms of v-P3k from and also deletions of 13 and amino the amino terminus of the P3k sequences. that deletions but are to a myristylation or a farnesylation signal are the acid amino-terminal deletion into c-P3k to the transforming of this The amino-terminal deletions in the two forms of v-P3k are sufficient for oncogenicity. The Gag sequences by the mutant are from an avian Gag sequences of S. J. PubMed Google Scholar), are not J.W. J. 1989; PubMed Google Scholar). shown that the amino-terminal of the avian retroviral Gag protein functions as a J.W. J. 1996; PubMed Google Scholar, R.B. Vogt J. 1984; PubMed Google Scholar). 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The deleted sequences and domains of P3k or they be that the active of the These results are in with a on the of amino-terminal and deletions on the kinase activity of constitutively active p110α that P3k a amino-terminal probably its activity is of interaction with p85 A. Williams L.T. Science. 1995; PubMed Scopus Google Scholar). of the kinase by amino acid in the kinase or by the deletion of the kinase in a the protein is to cellular by a myristylation These that constitutive kinase activity of P3k is and sufficient for membrane localization or not be but in the of kinase activity is not sufficient to the oncogenicity of P3k. analysis also two of P3k from the transformation p85 and The v-P3k protein by a acid amino-terminal deletion and bind p85, it is transforming and kinase activity is than that of v-P3k from which p85 binding shown that p85 can the lipid kinase activity of J. Y. J. T. Mol. Cell. Biol. 1998; 18: PubMed Google Scholar). Ras can bind to the of amino acids to in P3k and can the kinase A to of P3k shown to with Ras binding (13.Rodriguez-Viciana P. Warne P.H. Vanhaesebroeck B. Waterfield M.D. Downward J. EMBO J. 1996; 15: 2442-2451Crossref PubMed Scopus (501) Google Scholar) this mutant is binding to Ras does not a role in transformation. A downstream of PI 3-kinase, can also induce transformation in CEF cultures and hemangiosarcomas in chickens M. Bellacosa A. Tsichlis P. Vogt P.K. Proc. Natl. Acad. Sci. U. S. A. 1998; PubMed Scopus Google Scholar). localization and kinase activity are for transforming mutants of Akt with transformation suggesting that Akt is a component of the oncogenic signal by P3k M. Bellacosa A. Tsichlis P. Vogt P.K. Proc. Natl. Acad. Sci. U. S. A. 1998; PubMed Scopus Google Scholar). The for this P3k and Akt by a oncogenicity of a P3k and activating phosphorylation of Akt and by that Akt is constitutively active in of growth factor and to another downstream of PI 3-kinase A. C. 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Aoki et al. (Wed,) studied this question.
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