Activation of PI3Kα by physiological effectors and by oncogenic mutations: structural and dynamic effects

Abstract

PI3Kα, a heterodimeric lipid kinase, catalyzes the conversion of phosphoinositide-4,5-bisphosphate (PIP2) to phosphoinositide-3,4,5-trisphosphate (PIP3), a lipid that recruits to the plasma membrane proteins that regulate signaling cascades that control key cellular processes such as cell proliferation, carbohydrate metabolism, cell motility, and apoptosis. PI3Kα is composed of two subunits, p110α and p85, that are activated by binding to phosphorylated receptor tyrosine kinases (RTKs) or their substrates. The gene coding for p110α, PIK3CA, has been found to be mutated in a large number of tumors; these mutations result in increased PI3Kα kinase activity. The structure of the complex of p110α with a fragment of p85 containing the nSH2 and the iSH2 domains has provided valuable information about the mechanisms underlying the physiological activation of PI3Kα and its pathological activation by oncogenic mutations. This review discusses information derived from x-ray diffraction and theoretical calculations regarding the structural and dynamic effects of mutations in four highly mutated regions of PI3K p110α, as well as the proposed mechanisms by which these mutations increase kinase activity. During the physiological activation of PI3Kα, the phosphorylated tyrosine of RTKs binds to the nSH2 domain of p85, dislodging an inhibitory interaction between the p85 nSH2 and a loop of the helical domain of p110α. Several of the oncogenic mutations in p110α activate the enzyme by weakening this autoinhibitory interaction. These effects involve structural changes as well as changes in the dynamics of the enzyme. One of the most common p110α mutations, H1047R, activates PI3Kα by a different mechanism: it increases the interaction of the enzyme with the membrane, maximizing the access of the PI3Kα to its substrate PIP2, a membrane lipid.

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References

  1. Atilgan A, Durell S et al (2001) Anisotropy of fluctuation dynamics of proteins iwth an elastic network model. Biophys J 80(1):505–515

    CAS  Article  PubMed Central  PubMed  Google Scholar 

  2. Bachman KE, Argani P et al (2004) The PIK3CA gene is mutated with high frequency in human breast cancers. Cancer Biol Ther 3(8):772–775

    CAS  Article  PubMed  Google Scholar 

  3. Berndt A, Miller S et al (2010) The p110delta structure: mechanisms for selectivity and potency of new PI(3)K inhibitors. Nat Chem Biol 6(3):244

    CAS  Article  PubMed  Google Scholar 

  4. Broderick DK, Di C et al (2004) Mutations of PIK3CA in anaplastic oligodendrogliomas, high-grade astrocytomas, and medulloblastomas. Cancer Res 64(15):5048–5050

    CAS  Article  PubMed  Google Scholar 

  5. Burke JE, Perisic O et al (2012) Oncogenic mutations mimic and enhance dynamic events in the natural activation of phosphoinositide 3-kinase p110alpha (PIK3CA). Proc Natl Acad Sci USA 109(38):15259–15264In this paper the dynamics of PI3K are analyzed by hydrogen deuterium exchange mass spectrometry. It Identifies regions of enhanced dynamics in the heterodimer.

    CAS  Article  PubMed Central  PubMed  Google Scholar 

  6. Burke JE, Vadas O et al (2011) Dynamics of the phosphoinositide 3-kinase p110delta interaction with p85alpha and membranes reveals aspects of regulation distinct from p110alpha. Structure 19(8):1127–1137

    CAS  Article  PubMed Central  PubMed  Google Scholar 

  7. Campbell IG, Russell SE et al (2004) Mutation of the PIK3CA gene in ovarian and breast cancer. Cancer Res 64(21):7678–7681

    CAS  Article  PubMed  Google Scholar 

  8. Carson JD, Van Aller G et al (2008) Effects of oncogenic p110alpha subunit mutations on the lipid kinase activity of phosphoinositide 3-kinase. Biochem J 409(2):519–524

    CAS  Article  PubMed  Google Scholar 

  9. Certal V, Halley F et al (2012) Discovery and optimization of new benzimidazole- and benzoxazole-pyrimidone selective PI3Kbeta inhibitors for the treatment of phosphatase and TENsin homologue (PTEN)-deficient cancers. J Med Chem 55(10):4788–4805

    CAS  Article  PubMed  Google Scholar 

  10. Cgarn CGARN (2008) Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455(7216):1061–1068

    Article  Google Scholar 

  11. Dhand R, Hara K et al (1994) PI 3-kinase: structural and functional analysis of intersubunit interactions. EMBO J 13(3):511–521

    CAS  PubMed Central  PubMed  Google Scholar 

  12. Engelman JA, Luo J et al (2006) The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet 7(8):606–619

    CAS  Article  PubMed  Google Scholar 

  13. Eyal, E., A. Dutta, et al. (2011) Cooperative dynamics of proteins unraveled by network models. WIREs Computational Molecular Science 1 (May-June)

  14. Forbes SA, Bindal N et al (2011) COSMIC: mining complete cancer genomes in the Catalogue of Somatic Mutations in Cancer.. Nucleic Acids Res 39(Database issue):D945–D950

    CAS  Article  PubMed Central  PubMed  Google Scholar 

  15. Gabelli SB, Mandelker D et al (2010) Somatic mutations in PI3Kalpha: structural basis for enzyme activation and drug design. Biochim Biophys Acta 1804(3):533–540

    CAS  Article  PubMed Central  PubMed  Google Scholar 

  16. Geering B, Cutillas PR et al (2007) Class IA phosphoinositide 3-kinases are obligate p85-p110 heterodimers. Proc Natl Acad Sci USA 104(19):7809–7814

    CAS  Article  PubMed Central  PubMed  Google Scholar 

  17. Gur M, Zomot E et al (2013) Global motions exhibited by proteins in micro- to milliseconds simulations concur with anisotropic network model predictions. J Chem Phys 139(121912)

  18. Gymnopoulos M, Elsliger MA et al (2007) Rare cancer-specific mutations in PIK3CA show gain of function. Proc Natl Acad Sci USA 104(13):5569–5574

    CAS  Article  PubMed Central  PubMed  Google Scholar 

  19. Holt KH, Olson L et al (1994) Phosphatidylinositol 3-kinase activation is mediated by high-affinity interactions between distinct domains within the p110 and p85 subunits. Mol Cell Biol 14(1):42–49

    CAS  PubMed Central  PubMed  Google Scholar 

  20. Hon WC, Berndt A et al (2012) Regulation of lipid binding underlies the activation mechanism of class IA PI3-kinases. Oncogene 31(32):3655–3666

    CAS  Article  PubMed Central  PubMed  Google Scholar 

  21. Huang CH, Mandelker D et al (2007) The structure of a human p110alpha/p85alpha complex elucidates the effects of oncogenic PI3Kalpha mutations. Science 318(5857):1744–1748 This paper describes the structure of the p110/nip85 heterodimer and identifies the high mutation regions in the structure.

    CAS  Article  PubMed  Google Scholar 

  22. Kang S, Bader AG et al (2004) Phosphatidylinositol 3-kinase mutations identified in human cancer are oncogenic. Proc Natl Acad Sci USA 102(3):802–807

    Article  Google Scholar 

  23. Katso R, Okkenhaug K et al (2001) Cellular function of phosphoinositide 3-kinases: implications for development, homeostasis, and cancer. Annu Rev Cell Dev Biol 17:615–675

    CAS  Article  PubMed  Google Scholar 

  24. Lee JW, Soung YH et al (2005) PIK3CA gene is frequently mutated in breast carcinomas and hepatocellular carcinomas. Oncogene 24(8):1477–1480

    CAS  Article  PubMed  Google Scholar 

  25. Levine DA, Bogomolniy F et al (2005) Frequent mutation of the PIK3CA gene in ovarian and breast cancers. Clin Cancer Res 11(8):2875–2878

    CAS  Article  PubMed  Google Scholar 

  26. Mandelker D, Gabelli SB et al (2009) A frequent kinase domain mutation that changes the interaction between PI3Kalpha and the membrane. Proc Natl Acad Sci U S A 106(40):16996–17001

    CAS  Article  PubMed Central  PubMed  Google Scholar 

  27. Miled N, Yan Y et al (2007) Mechanism of two classes of cancer mutations in the phosphoinositide 3-kinase catalytic subunit. Science 317(5835):239–242

    CAS  Article  PubMed  Google Scholar 

  28. Murray JM, Sweeney ZK et al (2012) Potent and highly selective benzimidazole inhibitors of PI3-kinase delta. J Med Chem 55(17):7686–7695

    CAS  Article  PubMed  Google Scholar 

  29. Nolte RT, Eck MJ et al (1996) “Crystal structure of the PI 3-kinase p85 amino-terminal SH2 domain and its phosphopeptide complexes”. Nat Struct Biol 3(4):364–374

    CAS  Article  PubMed  Google Scholar 

  30. Rudd ML, Price JC et al (2011) A unique spectrum of somatic PIK3CA (p110alpha) mutations within primary endometrial carcinomas. Clin Cancer Res 17(6):1331–1340

    CAS  Article  PubMed Central  PubMed  Google Scholar 

  31. Samuels Y, Wang Z et al (2004) High frequency of mutations of the PIK3CA gene in human cancers. Science 304(5670):554

    CAS  Article  PubMed  Google Scholar 

  32. Shepherd PR, Siddle K et al (1997) Is stimulation of class-1 phosphatidylinositol 3-kinase activity by insulin sufficient to activate pathways involved in glucose metabolism. Biochem Soc Trans 25(3):978–981

    CAS  PubMed  Google Scholar 

  33. Vanhaesebroeck B, Alessi DR (2000) The PI3K-PDK1 connection: more than just a road to PKB. Biochem J 346(Pt 3):561–576

    CAS  Article  PubMed Central  PubMed  Google Scholar 

  34. Vanhaesebroeck B, Waterfield MD (1999) Signaling by distinct classes of phosphoinositide 3-kinases. Exp Cell Res 253(1):239–254

    CAS  Article  PubMed  Google Scholar 

  35. Vogt PK, Kang S et al (2007) Cancer-specific mutations in phosphatidylinositol 3-kinase. Trends Biochem Sci 32(7):342–349

    CAS  Article  PubMed  Google Scholar 

  36. Walker EH, Perisic O et al (1999) Structural insights into phosphoinositide 3-kinase catalysis and signalling. Nature 402(6759):313–320

    CAS  Article  PubMed  Google Scholar 

  37. Wu H, Yan Y et al (2007) Regulation of class IA PI3Ks. Biochem Soc Trans 35(Pt 2):242–244

    CAS  PubMed  Google Scholar 

  38. Zhao L, Vogt PK (2008a) Class I PI3K in oncogenic cellular transformation. Oncogene 27(41):5486–5496

    CAS  Article  PubMed Central  PubMed  Google Scholar 

  39. Zhao L, Vogt PK (2008b) Helical domain and kinase domain mutations in p110alpha of phosphatidylinositol 3-kinase induce gain of function by different mechanisms. Proc Natl Acad Sci USA 105(7):2652–2657

    CAS  Article  PubMed Central  PubMed  Google Scholar 

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Acknowledgments

This work was supported by the Virginia and D.K. Ludwig Fund for Cancer Research and by NIH grant CA43460. SBG is a Stewart Trust fellow.

Conflict of interest

Authors Sandra B. Gabelli, Ignacia Echeverria, Megan Alexander, Krisna C. Duong-Ly, Daniele Chaves-Moreira, Evan T. Brower, B. Vogelstein, and L. Mario Amzel declare that they have no conflict of interest.

This article does not contain any studies with human or animal subjects performed by the any of the authors.

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Correspondence to Sandra B. Gabelli or L. Mario Amzel.

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Special Issue Advances in Biophysics in Latin America

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Gabelli, S.B., Echeverria, I., Alexander, M. et al. Activation of PI3Kα by physiological effectors and by oncogenic mutations: structural and dynamic effects. Biophys Rev 6, 89–95 (2014). https://doi.org/10.1007/s12551-013-0131-1

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Keywords

  • PIK3R1
  • p85
  • PIK3CA
  • PI3K
  • Somatic mutation
  • PIP2
  • PIP3