Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Progress
  • Published:

Structural comparisons of class I phosphoinositide 3-kinases

Nature Reviews Cancer volume 8, pages 665–669 (2008)Cite this article

Abstract

Class I phosphoinositide 3-kinases (PI3Ks) are lipid kinases that regulate cell growth. One of these kinases, PI3Kα, is frequently mutated in diverse tumour types. The recently determined structure of PI3Kα reveals features that distinguish this enzyme from related lipid kinases. In addition, wild-type PI3Kγ differs from PI3Kα by a substitution identical to a PI3Kα oncogenic mutant (His1047Arg) that might explain the differences in the enzymatic activities of the normal and mutant PI3Kα. Comparison of the PI3K structures also identified structural features that could potentially be exploited for the design of isoform-specific inhibitors.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Comparison of the Ras-binding domains (RBDs) of p110α and p110γ.
Figure 2: comparison between the c2 domains of p110α and p110γ.
Figure 3: Comparison between the kinase domains of p110α and p110γ.

Similar content being viewed by others

References

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

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Bader, A. G., Kang, S., Zhao, L. & Vogt, P. K. Oncogenic PI3K deregulates transcription and translation. Nature Rev. Cancer 5, 921–929 (2005).

    Article  CAS  Google Scholar 

  3. Vivanco, I. & Sawyers, C. L. The phosphatidylinositol 3-kinase AKT pathway in human cancer. Nature Rev. Cancer 2, 489–501 (2002).

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  5. Engelman, J. A., Luo, J. & Cantley, L. C. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nature Rev. Genet. 7, 606–619 (2006).

    Article  CAS  PubMed  Google Scholar 

  6. Vogt, P. K., Bader, A. G. & Kang, S. Phosphoinositide 3-kinase: from viral oncoprotein to drug target. Virology 344, 131–138 (2006).

    Article  CAS  PubMed  Google Scholar 

  7. Chang, H. W. et al. Transformation of chicken cells by the gene encoding the catalytic subunit of PI 3-kinase. Science 276, 1848–1850 (1997).

    Article  CAS  PubMed  Google Scholar 

  8. Li, J. et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 275, 1943–1947 (1997).

    Article  CAS  PubMed  Google Scholar 

  9. Sansal, I. & Sellers, W. R. The biology and clinical relevance of the PTEN tumor suppressor pathway. J. Clin. Oncol. 22, 2954–2963 (2004).

    Article  CAS  PubMed  Google Scholar 

  10. Steck, P. A. et al. Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nature Genet. 15, 356–362 (1997).

    Article  CAS  PubMed  Google Scholar 

  11. Bachman, K. E. et al. The PIK3CA gene is mutated with high frequency in human breast cancers. Cancer Biol. Ther. 3, 772–775 (2004).

    Article  CAS  PubMed  Google Scholar 

  12. Broderick, D. K. et al. Mutations of PIK3CA in anaplastic oligodendrogliomas, high-grade astrocytomas, and medulloblastomas. Cancer Res. 64, 5048–5050 (2004).

    Article  CAS  PubMed  Google Scholar 

  13. Campbell, I. G. et al. Mutation of the PIK3CA gene in ovarian and breast cancer. Cancer Res. 64, 7678–7681 (2004).

    Article  CAS  PubMed  Google Scholar 

  14. Lee, J. W. et al. PIK3CA gene is frequently mutated in breast carcinomas and hepatocellular carcinomas. Oncogene 24, 1477–1480 (2005).

    Article  CAS  PubMed  Google Scholar 

  15. Levine, D. A. et al. Frequent mutation of the PIK3CA gene in ovarian and breast cancers. Clin. Cancer Res. 11, 2875–2878 (2005).

    Article  CAS  PubMed  Google Scholar 

  16. Saal, L. H. et al. PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma. Cancer Res. 65, 2554–2559 (2005).

    Article  CAS  PubMed  Google Scholar 

  17. Samuels, Y. et al. High frequency of mutations of the PIK3CA gene in human cancers. Science 304, 554 (2004).

    Article  CAS  PubMed  Google Scholar 

  18. Vogt, P. K., Kang, S., Elsliger, M. A. & Gymnopoulos, M. Cancer-specific mutations in phosphatidylinositol 3-kinase. Trends Biochem. Sci. 32, 342–349 (2007).

    Article  CAS  PubMed  Google Scholar 

  19. Wang, Y., Helland, A., Holm, R., Kristensen, G. B. & Borresen-Dale, A. L. PIK3CA mutations in advanced ovarian carcinomas. Hum. Mutat. 25, 322 (2005).

    Article  CAS  PubMed  Google Scholar 

  20. Philp, A. J. et al. The phosphatidylinositol 3′-kinase p85α gene is an oncogene in human ovarian and colon tumors. Cancer Res. 61, 7426–7429 (2001).

    CAS  PubMed  Google Scholar 

  21. Knight, Z. A. & Shokat, K. M. Chemically targeting the PI3K family. Biochem. Soc. Trans. 35, 245–249 (2007).

    Article  CAS  PubMed  Google Scholar 

  22. Pacold, M. E. et al. Crystal structure and functional analysis of Ras binding to its effector phosphoinositide 3-kinase γ. Cell 103, 931–943 (2000).

    Article  CAS  PubMed  Google Scholar 

  23. Walker, E. H. et al. Structural determinants of phosphoinositide 3-kinase inhibition by wortmannin, LY294002, quercetin, myricetin, and staurosporine. Mol. Cell 6, 909–919 (2000).

    Article  CAS  PubMed  Google Scholar 

  24. Walker, E. H., Perisic, O., Ried, C., Stephens, L. & Williams, R. L. Structural insights into phosphoinositide 3-kinase catalysis and signalling. Nature 402, 313–320 (1999).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  26. Huang, C. H. et al. The structure of a human p110α/p85α complex elucidates the effects of oncogenic PI3Kα mutations. Science 318, 1744–1748 (2007).

    Article  CAS  PubMed  Google Scholar 

  27. Stephens, L. R. et al. The G β γ sensitivity of a PI3K is dependent upon a tightly associated adaptor, p101. Cell 89, 105–114 (1997).

    Article  CAS  PubMed  Google Scholar 

  28. Suire, S. et al. p84, a new Gβγ-activated regulatory subunit of the type IB phosphoinositide 3-kinase p110γ. Curr. Biol. 15, 566–570 (2005).

    Article  CAS  PubMed  Google Scholar 

  29. Voigt, P., Brock, C., Nurnberg, B. & Schaefer, M. Assigning functional domains within the p101 regulatory subunit of phosphoinositide 3-kinase γ. J. Biol. Chem. 280, 5121–5127 (2005).

    Article  CAS  PubMed  Google Scholar 

  30. Yu, J., Wjasow, C. & Backer, J. M. Regulation of the p85/p110α phosphatidylinositol 3′-kinase. Distinct roles for the N-terminal and C-terminal SH2 domains. J. Biol. Chem. 273, 30199–30203 (1998).

    Article  CAS  PubMed  Google Scholar 

  31. Carson, J. D. et al. Effects of oncogenic p110α subunit mutations on the lipid kinase activity of phosphoinositide 3-kinase. Biochem. J. 409, 519–524 (2008).

    Article  CAS  PubMed  Google Scholar 

  32. Bondeva, T. et al. Bifurcation of lipid and protein kinase signals of PI3Kγ to the protein kinases PKB and MAPK. Science 282, 293–296 (1998).

    Article  CAS  PubMed  Google Scholar 

  33. Pirola, L. et al. Activation loop sequences confer substrate specificity to phosphoinositide 3-kinase α (PI3Kα). Functions of lipid kinase-deficient PI3Kα in signaling. J. Biol. Chem. 276, 21544–21554 (2001).

    Article  CAS  PubMed  Google Scholar 

  34. Kang, S., Bader, A. G. & Vogt, P. K. Phosphatidylinositol 3-kinase mutations identified in human cancer are oncogenic. Proc. Natl Acad. Sci. USA 102, 802–807 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Ikenoue, T. Functional analysis of PIK3CA gene mutations in human colorectal cancer. Cancer Res. 65, 4562–4567 (2005).

    Article  CAS  PubMed  Google Scholar 

  36. Knight, Z. A. et al. A pharmacological map of the PI3-K family defines a role for p110α in insulin signaling. Cell 125, 733–747 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Support was provided by the Virginia and D. K. Ludwig Fund for Cancer Research, NIH grants CA43460 to B.V., GM066895 to L.M.A, and GM07309 and GM07184 to D.M.

Author information

Author notes

  1. L. Mario Amzel and Chuan-Hsiang Huang: L.M.A and C.-H.H. contributed equally to this work.

Authors and Affiliations

  1. Chuan-Hsiang Huang and Sandra B. Gabelli are at the Department of Biophysics and Biophysical Chemistry,Johns Hopkins University School of Medicine, L. Mario Amzel, 725 North Wolfe Street, Baltimore, Maryland 21205, USA.,

    L. Mario Amzel, Chuan-Hsiang Huang & Sandra B. Gabelli

  2. Chuan-Hsiang Huang is at the Graduate Program in Immunology, Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, Maryland 21205, USA.,

    Chuan-Hsiang Huang

  3. Diana Mandelker, Christoph Lengauer and Bert Vogelstein are at the Ludwig Center for Cancer Genetics and Therapeutics, and The Howard Hughes Medical Institute at The Johns Hopkins Kimmel Cancer Center, 1,650 Orleans Street, Baltimore, Maryland 21231, USA.,

    Diana Mandelker, Christoph Lengauer & Bert Vogelstein

  4. Christoph Lengauer is currently at the Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, 02139, Massachusetts, USA

    Christoph Lengauer

Authors
  1. L. Mario Amzel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chuan-Hsiang Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Diana Mandelker
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Christoph Lengauer
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sandra B. Gabelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Bert Vogelstein
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bert Vogelstein.

Ethics declarations

Competing interests

Under agreements between the Johns Hopkins Universtiy and Exact Sciences, Inc., B. V. is entitled to a share of the royalties received by the University on sales of products related to PIK3CA mutations. The University and B. V. also own stock in Exact Sciences, Inc., which is subject to certain restrictions under University policy. The terms of these arrangements are being managed by the University in accordance with its conflict of interest policies.

Supplementary information

Related links

Related links

DATABASES

National Cancer Institute

brain tumour

breast cancer

colon cancer

liver cancer

ovarian cancer

FURTHER INFORMATION

L. Mario Amzel's homepage

Rights and permissions

Reprints and permissions

About this article

Cite this article

Amzel, L., Huang, CH., Mandelker, D. et al. Structural comparisons of class I phosphoinositide 3-kinases. Nat Rev Cancer 8, 665–669 (2008). https://doi.org/10.1038/nrc2443

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc2443

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing