The DOI matches its Crossref record; 4 of the 4 references it cites were found in a registry or an index.
A frequent kinase domain mutation that changes the interaction between PI3Kα and the membrane
Open accessAbstract
Mutations in oncogenes often promote tumorigenesis by changing the conformation of the encoded proteins, thereby altering enzymatic activity. The PIK3CA oncogene, which encodes p110α, the catalytic subunit of phosphatidylinositol 3-kinase alpha (PI3Kα), is one of the two most frequently mutated oncogenes in human cancers. We report the structure of the most common mutant of p110α in complex with two interacting domains of its regulatory partner (p85α), both free and bound to an inhibitor (wortmannin). The N-terminal SH2 (nSH2) domain of p85α is shown to form a scaffold for the entire enzyme complex, strategically positioned to communicate extrinsic signals from phosphopeptides to three distinct regions of p110α. Moreover, we found that Arg-1047 points toward the cell membrane, perpendicular to the orientation of His-1047 in the WT enzyme. Surprisingly, two loops of the kinase domain that contact the cell membrane shift conformation in the oncogenic mutant. Biochemical assays revealed that the enzymatic activity of the p110α His1047Arg mutant is differentially regulated by lipid membrane composition. These structural and biochemical data suggest a previously undescribed mechanism for mutational activation of a kinase that involves perturbation of its interaction with the cellular membrane.
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The Cancer Genome Atlas Research Network (2008) · Nature · doi:10.1038/nature07385 · Cited by 7,735
An Integrated Genomic Analysis of Human Glioblastoma Multiforme
Parsons, D. W., Jones, S., Zhang, X., Lin, J. C.-H., Leary, R. J., Angenendt, P., Mankoo, P., Carter, H., Siu, I.-M., Gallia, G. L., et al. (2008) · Science · doi:10.1126/science.1164382 · Cited by 5,857
Self-citationThe phosphoinositide 3-kinase pathway
Cantley, L. C. (2002) · Science · doi:10.1126/science.296.5573.1655 · Cited by 5,621
Erlotinib in Previously Treated Non–Small-Cell Lung Cancer
Shepherd, F. A., Rodrigues Pereira, J., Ciuleanu, T., Tan, E. H., Hirsh, V., Thongprasert, S., Campos, D., Maoleekoonpiroj, S., Smylie, M., Martins, R., et al. (2005) · New England Journal of Medicine · doi:10.1056/nejmoa050753 · Cited by 5,419
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Vanhaesebroeck, B., Guillermet-Guibert, J., Graupera, M., & Bilanges, B. (2010) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2882 · Cited by 1,767
Phosphoinositides: Tiny Lipids With Giant Impact on Cell Regulation
Balla, T. (2013) · Physiological Reviews · doi:10.1152/physrev.00028.2012 · Cited by 1,638
Acquired Resistance and Clonal Evolution in Melanoma during BRAF Inhibitor Therapy
Shi, H., Hugo, W., Kong, X., Hong, A., Koya, R. C., Moriceau, G., Chodon, T., Guo, R., Johnson, D. B., Dahlman, K. B., et al. (2014) · Cancer Discovery · doi:10.1158/2159-8290.cd-13-0642 · Cited by 982
Kim, K., Skora, A. D., Li, Z., Liu, Q., Tam, A. J., Blosser, R. L., Diaz, L. A., Papadopoulos, N., Kinzler, K. W., Vogelstein, B., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1410626111 · Cited by 676
Self-citationThe landscape of somatic mutations in infant MLL-rearranged acute lymphoblastic leukemias
for The St. Jude Children's Research Hospital–Washington University Pediatric Cancer Genome Project, Andersson, A. K., Ma, J., Wang, J., Chen, X., Gedman, A. L., Dang, J., Nakitandwe, J., Holmfeldt, L., Parker, M., et al. (2015) · Nature Genetics · doi:10.1038/ng.3230 · Cited by 490
Metadata
- Authors
- Mandelker, D., Gabelli, S. B., Schmidt-Kittler, O., Zhu, J., Cheong, I., Huang, C.-H., Kinzler, K. W., Vogelstein, B., & Amzel, L. M.
- Venue
- Proceedings of the National Academy of Sciences
- Published
- 2009-10-06
- Volume
- 106
- Issue
- 40
- Pages
- 16996-17001
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- OpenAlex
- W2090038231
- Cited by
- 293
- References
- 4
- FWCI
- 6.96
- Type
- journal article
- Language
- en
- Open access
- green
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- Mandelker, D., Gabelli, S. B., Schmidt-Kittler, O., Zhu, J., Cheong, I., Huang, C.-H., Kinzler, K. W., Vogelstein, B., & Amzel, L. M. (2009). A frequent kinase domain mutation that changes the interaction between PI3Kα and the membrane. Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.0908444106
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