A frequent kinase domain mutation that changes the interaction between PI3Kα and the membrane

Diana Mandelker, Sandra B. Gabelli, Oleg Schmidt-Kittler, Jiuxiang Zhu, Ian Cheong, Chuan Hsiang Huang, Kenneth W. Kinzler, Bert Vogelstein, L. Mario Amzel

Research output: Contribution to journalArticlepeer-review

201 Scopus citations


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 p110αin 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.

Original languageEnglish (US)
Pages (from-to)16996-17001
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number40
StatePublished - Oct 6 2009


  • Mutant
  • Oncogene
  • p110
  • p85

ASJC Scopus subject areas

  • General


Dive into the research topics of 'A frequent kinase domain mutation that changes the interaction between PI3Kα and the membrane'. Together they form a unique fingerprint.

Cite this