title: Gain of interaction with IRS1 by p110α-helical domain mutants is crucial for their oncogenic functions.
abstract: PIK3CA, which encodes the p110α catalytic subunit of phosphatidylinositol 3-kinase α, is frequently mutated in human cancers. Most of these mutations occur at two hot-spots: E545K and H1047R located in the helical domain and the kinase domain, respectively. Here, we report that p110α E545K, but not p110α H1047R, gains the ability to associate with IRS1 independent of the p85 regulatory subunit, thereby rewiring this oncogenic signaling pathway. Disruption of the IRS1-p110α E545K interaction destabilizes the p110α protein, reduces AKT phosphorylation, and slows xenograft tumor growth of a cancer cell line expressing p110α E545K. Moreover, a hydrocarbon-stapled peptide that disrupts this interaction inhibits the growth of tumors expressing p110α E545K.
authors: Department of Genetics and Genome Sciences, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, USA.
authors: Yujun
authors: Y
authors: Hao
authors: Chao
authors: C
authors: Wang
authors: Bo
authors: B
authors: Cao
authors: Brett M
authors: BM
authors: Hirsch
authors: Jing
authors: J
authors: Song
authors: Sanford D
authors: SD
authors: Markowitz
authors: Rob M
authors: RM
authors: Ewing
authors: David
authors: D
authors: Sedwick
authors: Lili
authors: L
authors: Liu
authors: Weiping
authors: W
authors: Zheng
authors: Zhenghe
authors: Z
authors: Wang
mesh_terms: D019943:Amino Acid Substitution; D045744:Cell Line, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000737:chemistry / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D025941:Protein Interaction Mapping; D017434:Protein Structure, Tertiary; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism
chemical_list: C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D051057:Proto-Oncogene Proteins c-akt
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