Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

Science 318 (5857): 1744-1748

Copyright © 2007 by the American Association for the Advancement of Science

The Structure of a Human p110{alpha}/p85{alpha} Complex Elucidates the Effects of Oncogenic PI3K{alpha} Mutations

Chuan-Hsiang Huang,1,3 Diana Mandelker,2 Oleg Schmidt-Kittler,2 Yardena Samuels,2* Victor E. Velculescu,2 Kenneth W. Kinzler,2 Bert Vogelstein,2{dagger} Sandra B. Gabelli,1{dagger} L. Mario Amzel1{dagger}

Abstract: PIK3CA, one of the two most frequently mutated oncogenes in human tumors, codes for p110{alpha}, the catalytic subunit of a phosphatidylinositol 3-kinase, isoform {alpha} (PI3K{alpha}, p110{alpha}/p85). Here, we report a 3.0 angstrom resolution structure of a complex between p110{alpha} and a polypeptide containing the p110{alpha}-binding domains of p85{alpha}, a protein required for its enzymatic activity. The structure shows that many of the mutations occur at residues lying at the interfaces between p110{alpha} and p85{alpha} or between the kinase domain of p110{alpha} and other domains within the catalytic subunit. Disruptions of these interactions are likely to affect the regulation of kinase activity by p85 or the catalytic activity of the enzyme, respectively. In addition to providing new insights about the structure of PI3K{alpha}, these results suggest specific mechanisms for the effect of oncogenic mutations in p110{alpha} and p85{alpha}.

1 Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
2 Ludwig Center for Cancer Genetics and Therapeutics, and Howard Hughes Medical Institute at the Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21231, USA.
3 Graduate Program in Immunology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

* Present address: National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.

{dagger} To whom correspondence should be addressed. E-mail: mamzel{at}jhmi.edu (L.M.A.); gabelli{at}jhmi.edu (S.B.G.); vogelbe{at}jhmi.edu (B.V.)


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
High-Throughput Detection of Clinically Relevant Mutations in Archived Tumor Samples by Multiplexed PCR and Next-Generation Sequencing.
R. Bourgon, S. Lu, Y. Yan, M. R. Lackner, W. Wang, V. Weigman, D. Wang, Y. Guan, L. Ryner, H. Koeppen, et al. (2014)
Clin. Cancer Res. 20, 2080-2091
   Abstract »    Full Text »    PDF »
The Structural Basis of PI3K Cancer Mutations: From Mechanism to Therapy.
S. Liu, S. Knapp, and A. A. Ahmed (2014)
Cancer Res. 74, 641-646
   Abstract »    Full Text »    PDF »
Targeting the Protein-Protein Interaction between IRS1 and Mutant p110{alpha} for Cancer Therapy.
Y. Hao, S. Zhao, and Z. Wang (2014)
Toxicol Pathol 42, 140-147
   Abstract »    Full Text »    PDF »
Phosphoinositides: Tiny Lipids With Giant Impact on Cell Regulation.
T. Balla (2013)
Physiol Rev 93, 1019-1137
   Abstract »    Full Text »    PDF »
Characterization of Heparanase-induced Phosphatidylinositol 3-Kinase-AKT Activation and Its Integrin Dependence.
A. Riaz, N. Ilan, I. Vlodavsky, J.-P. Li, and S. Johansson (2013)
J. Biol. Chem. 288, 12366-12375
   Abstract »    Full Text »    PDF »
Somatic gain-of-function mutations in PIK3CA in patients with macrodactyly.
J. J. Rios, N. Paria, D. K. Burns, B. A. Israel, R. Cornelia, C. A. Wise, and M. Ezaki (2013)
Hum. Mol. Genet. 22, 444-451
   Abstract »    Full Text »    PDF »
Markers for Efficacy of Mammalian Target of Rapamycin Inhibitor.
Y.-M. LIAO, A. SY, and Y. YEN (2012)
Anticancer Res 32, 4235-4244
   Abstract »    Full Text »    PDF »
Oncogenic mutations mimic and enhance dynamic events in the natural activation of phosphoinositide 3-kinase p110{alpha} (PIK3CA).
J. E. Burke, O. Perisic, G. R. Masson, O. Vadas, and R. L. Williams (2012)
PNAS 109, 15259-15264
   Abstract »    Full Text »    PDF »
PI3 Kinase Inhibitors in the Clinic: An Update.
J.-E. KURTZ and I. RAY-COQUARD (2012)
Anticancer Res 32, 2463-2470
   Abstract »    Full Text »    PDF »
PI3K{delta} Inhibitors in Cancer: Rationale and Serendipity Merge in the Clinic.
D. A. Fruman and C. Rommel (2011)
Cancer Discovery 1, 562-572
   Abstract »    Full Text »    PDF »
Structural Basis for Activation and Inhibition of Class I Phosphoinositide 3-Kinases.
O. Vadas, J. E. Burke, X. Zhang, A. Berndt, and R. L. Williams (2011)
Science Signaling 4, re2
   Abstract »    Full Text »    PDF »
Using Tandem Mass Spectrometry in Targeted Mode to Identify Activators of Class IA PI3K in Cancer.
X. Yang, A. B. Turke, J. Qi, Y. Song, B. N. Rexer, T. W. Miller, P. A. Janne, C. L. Arteaga, L. C. Cantley, J. A. Engelman, et al. (2011)
Cancer Res. 71, 5965-5975
   Abstract »    Full Text »    PDF »
Inhibition of PI3K binding to activators by serine phosphorylation of PI3K regulatory subunit p85{alpha} Src homology-2 domains.
J. Y. Lee, Y.-H. Chiu, J. Asara, and L. C. Cantley (2011)
PNAS 108, 14157-14162
   Abstract »    Full Text »    PDF »
High Frequency of PIK3R1 and PIK3R2 Mutations in Endometrial Cancer Elucidates a Novel Mechanism for Regulation of PTEN Protein Stability.
L. W. T. Cheung, B. T. Hennessy, J. Li, S. Yu, A. P. Myers, B. Djordjevic, Y. Lu, K. Stemke-Hale, M. D. Dyer, F. Zhang, et al. (2011)
Cancer Discovery 1, 170-185
   Abstract »    Full Text »    PDF »
PIK3R1 (p85{alpha}) Is Somatically Mutated at High Frequency in Primary Endometrial Cancer.
M. E. Urick, M. L. Rudd, A. K. Godwin, D. Sgroi, M. Merino, and D. W. Bell (2011)
Cancer Res. 71, 4061-4067
   Abstract »    Full Text »    PDF »
Nuclear but Not Cytosolic Phosphoinositide 3-Kinase Beta Has an Essential Function in Cell Survival.
A. Kumar, J. Redondo-Munoz, V. Perez-Garcia, I. Cortes, M. Chagoyen, and A. C. Carrera (2011)
Mol. Cell. Biol. 31, 2122-2133
   Abstract »    Full Text »    PDF »
Cooperation between Pik3ca and p53 Mutations in Mouse Mammary Tumor Formation.
J. R. Adams, K. Xu, J. C. Liu, N. M. R. Agamez, A. J. Loch, R. G. Wong, W. Wang, K. L. Wright, T. F. Lane, E. Zacksenhaus, et al. (2011)
Cancer Res. 71, 2706-2717
   Abstract »    Full Text »    PDF »
A Unique Spectrum of Somatic PIK3CA (p110{alpha}) Mutations Within Primary Endometrial Carcinomas.
M. L. Rudd, J. C. Price, S. Fogoros, A. K. Godwin, D. C. Sgroi, M. J. Merino, and D. W. Bell (2011)
Clin. Cancer Res. 17, 1331-1340
   Abstract »    Full Text »    PDF »
A biochemical mechanism for the oncogenic potential of the p110{beta} catalytic subunit of phosphoinositide 3-kinase.
H. A. Dbouk, H. Pang, A. Fiser, and J. M. Backer (2010)
PNAS 107, 19897-19902
   Abstract »    Full Text »    PDF »
PI3K/PTEN/Akt pathway status affects the sensitivity of high-grade glioma cell cultures to the insulin-like growth factor-1 receptor inhibitor NVP-AEW541.
D. Hagerstrand, M. B. Lindh, C. Pena, C. Garcia-Echeverria, M. Nister, F. Hofmann, and A. Ostman (2010)
Neuro Oncology 12, 967-975
   Abstract »    Full Text »    PDF »
Cancer-derived mutations in the regulatory subunit p85{alpha} of phosphoinositide 3-kinase function through the catalytic subunit p110{alpha}.
M. Sun, P. Hillmann, B. T. Hofmann, J. R. Hart, and P. K. Vogt (2010)
PNAS 107, 15547-15552
   Abstract »    Full Text »    PDF »
New Strategies in Colorectal Cancer: Biomarkers of Response to Epidermal Growth Factor Receptor Monoclonal Antibodies and Potential Therapeutic Targets in Phosphoinositide 3-Kinase and Mitogen-Activated Protein Kinase Pathways.
A. Dasari and W. A. Messersmith (2010)
Clin. Cancer Res. 16, 3811-3818
   Abstract »    Full Text »    PDF »
Disulfiram Treatment Facilitates Phosphoinositide 3-Kinase Inhibition in Human Breast Cancer Cells In vitro and In vivo.
H. Zhang, D. Chen, J. Ringler, W. Chen, Q. C. Cui, S. P. Ethier, Q. P. Dou, and G. Wu (2010)
Cancer Res. 70, 3996-4004
   Abstract »    Full Text »    PDF »
Shaping Development of Autophagy Inhibitors with the Structure of the Lipid Kinase Vps34.
S. Miller, B. Tavshanjian, A. Oleksy, O. Perisic, B. T. Houseman, K. M. Shokat, and R. L. Williams (2010)
Science 327, 1638-1642
   Abstract »    Full Text »    PDF »
Drugging the PI3 Kinome: From Chemical Tools to Drugs in the Clinic.
P. Workman, P. A. Clarke, F. I. Raynaud, and R. L.M. van Montfort (2010)
Cancer Res. 70, 2146-2157
   Abstract »    Full Text »    PDF »
The PI3K Pathway As Drug Target in Human Cancer.
K. D. Courtney, R. B. Corcoran, and J. A. Engelman (2010)
J. Clin. Oncol. 28, 1075-1083
   Abstract »    Full Text »    PDF »
Structural insights into phosphoinositide 3-kinase activation by the influenza A virus NS1 protein.
B. G. Hale, P. S. Kerry, D. Jackson, B. L. Precious, A. Gray, M. J. Killip, R. E. Randall, and R. J. Russell (2010)
PNAS 107, 1954-1959
   Abstract »    Full Text »    PDF »
Resistance to Trastuzumab in Breast Cancer.
P. R. Pohlmann, I. A. Mayer, and R. Mernaugh (2009)
Clin. Cancer Res. 15, 7479-7491
   Abstract »    Full Text »    PDF »
Regulation of Class IA PI 3-kinases: C2 domain-iSH2 domain contacts inhibit p85/p110{alpha} and are disrupted in oncogenic p85 mutants.
H. Wu, S. C. Shekar, R. J. Flinn, M. El-Sibai, B. S. Jaiswal, K. I. Sen, V. Janakiraman, S. Seshagiri, G. J. Gerfen, M. E. Girvin, et al. (2009)
PNAS 106, 20258-20263
   Abstract »    Full Text »    PDF »
Emerging common themes in regulation of PIKKs and PI3Ks.
H. Lempiainen and T. D. Halazonetis (2009)
EMBO J. 28, 3067-3073
   Abstract »    Full Text »    PDF »
A frequent kinase domain mutation that changes the interaction between PI3K{alpha} and the membrane.
D. Mandelker, S. B. Gabelli, O. Schmidt-Kittler, J. Zhu, I. Cheong, C.-H. Huang, K. W. Kinzler, B. Vogelstein, and L. M. Amzel (2009)
PNAS 106, 16996-17001
   Abstract »    Full Text »    PDF »
Spectrum of Phosphatidylinositol 3-Kinase Pathway Gene Alterations in Bladder Cancer.
F. M. Platt, C. D. Hurst, C. F. Taylor, W. M. Gregory, P. Harnden, and M. A. Knowles (2009)
Clin. Cancer Res. 15, 6008-6017
   Abstract »    Full Text »    PDF »
RGS16 Inhibits Breast Cancer Cell Growth by Mitigating Phosphatidylinositol 3-Kinase Signaling.
G. Liang, G. Bansal, Z. Xie, and K. M. Druey (2009)
J. Biol. Chem. 284, 21719-21727
   Abstract »    Full Text »    PDF »
A site-specific, multiplexed kinase activity assay using stable-isotope dilution and high-resolution mass spectrometry.
Y. Yu, R. Anjum, K. Kubota, J. Rush, J. Villen, and S. P. Gygi (2009)
PNAS 106, 11606-11611
   Abstract »    Full Text »    PDF »
PI3K{gamma} Adaptor Subunits Define Coupling to Degranulation and Cell Motility by Distinct PtdIns(3,4,5)P3 Pools in Mast Cells.
T. Bohnacker, R. Marone, E. Collmann, R. Calvez, E. Hirsch, and M. P. Wymann (2009)
Science Signaling 2, ra27
   Abstract »    Full Text »    PDF »
Blocking Phosphoinositide 3-Kinase Activity in Colorectal Cancer Cells Reduces Proliferation but Does Not Increase Apoptosis Alone or in Combination with Cytotoxic Drugs.
C. Martin-Fernandez, J. Bales, C. Hodgkinson, A. Welman, M. J. Welham, C. Dive, and C. J. Morrow (2009)
Mol. Cancer Res. 7, 955-965
   Abstract »    Full Text »    PDF »
Isoform-selective phosphoinositide 3'-kinase inhibitors inhibit CXCR4 signaling and overcome stromal cell-mediated drug resistance in chronic lymphocytic leukemia: a novel therapeutic approach.
M. Niedermeier, B. T. Hennessy, Z. A. Knight, M. Henneberg, J. Hu, A. V. Kurtova, W. G. Wierda, M. J. Keating, K. M. Shokat, and J. A. Burger (2009)
Blood 113, 5549-5557
   Abstract »    Full Text »    PDF »
Knockdown of Ron Kinase Inhibits Mutant Phosphatidylinositol 3-Kinase and Reduces Metastasis in Human Colon Carcinoma.
J. Wang, A. Rajput, J. L. C. Kan, R. Rose, X.-Q. Liu, K. Kuropatwinski, J. Hauser, A. Beko, I. Dominquez, E. A. Sharratt, et al. (2009)
J. Biol. Chem. 284, 10912-10922
   Abstract »    Full Text »    PDF »
PIK3CA Mutations and Copy Number Gains in Human Lung Cancers.
H. Yamamoto, H. Shigematsu, M. Nomura, W. W. Lockwood, M. Sato, N. Okumura, J. Soh, M. Suzuki, I. I. Wistuba, K. M. Fong, et al. (2008)
Cancer Res. 68, 6913-6921
   Abstract »    Full Text »    PDF »
Mechanism of Influenza A Virus NS1 Protein Interaction with the p85{beta}, but Not the p85{alpha}, Subunit of Phosphatidylinositol 3-Kinase (PI3K) and Up-regulation of PI3K Activity.
Y. Li, D. H. Anderson, Q. Liu, and Y. Zhou (2008)
J. Biol. Chem. 283, 23397-23409
   Abstract »    Full Text »    PDF »
Class 1A PI3K regulates vessel integrity during development and tumorigenesis.
T. L. Yuan, H. S. Choi, A. Matsui, C. Benes, E. Lifshits, J. Luo, J. V. Frangioni, and L. C. Cantley (2008)
PNAS 105, 9739-9744
   Abstract »    Full Text »    PDF »
Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity.
S.-M. Maira, F. Stauffer, J. Brueggen, P. Furet, C. Schnell, C. Fritsch, S. Brachmann, P. Chene, A. De Pover, K. Schoemaker, et al. (2008)
Mol. Cancer Ther. 7, 1851-1863
   Abstract »    Full Text »    PDF »
Helical domain and kinase domain mutations in p110{alpha} of phosphatidylinositol 3-kinase induce gain of function by different mechanisms.
L. Zhao and P. K. Vogt (2008)
PNAS 105, 2652-2657
   Abstract »    Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882