title: Targeting the protein-protein interaction between IRS1 and mutant p110α for cancer therapy.
abstract: Phosphoinositide-3-kinase, catalytic, alpha polypeptide, which encodes the catalytic p110α subunit of phosphatidylinositol 3-kinase α, is the most frequently mutated oncogene in human cancers. Targeting mutant p110α holds great promise for cancer therapy. However, it is challenging to develop p110α isoform-specific inhibitors. Most p110α mutations occur at two hot spot regions: an acidic cluster (E542, E545, and Q546) in the helical domain and a histidine residue (H1047) in the kinase domain. We recently discovered that p110α helical domain mutant proteins, but not the kinase domain mutant proteins, directly associate with insulin receptor substrate 1 (IRS1). Moreover, we demonstrated that disruption of protein-protein interaction between p110α helical domain mutant and IRS1 inhibits the growth of tumors with such mutations. The direct protein interaction between IRS1 and p110α helical domain mutants may provide a more accessible target for developing novel precision cancer therapy.
authors.affiliation: 1Department of Genetics and Genome Sciences, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Yujun
authors.initials: Y
authors.lastname: Hao
authors.forename: Shuliang
authors.initials: S
authors.lastname: Zhao
authors.forename: Zhenghe
authors.initials: Z
authors.lastname: Wang
mesh_terms: D020134:Catalytic Domain; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics* / Q000378:metabolism; D058990:Molecular Targeted Therapy; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation; D009369:Neoplasms / Q000235:genetics / Q000628:therapy*; D009857:Oncogenes; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism; D054730:Protein Interaction Domains and Motifs / Q000502:physiology*; D015398:Signal Transduction
chemical_list: C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; D050505:Mutant Proteins; D019869:Phosphatidylinositol 3-Kinases
keywords: cancer; genomics.; molecular biology