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: Yujun Hao, Shuliang Zhao, Zhenghe Wang
• Journal: Toxicologic pathology (Toxicol Pathol) Vol. 42 Issue 1 Pg. 140-7 (Jan 2014) ISSN: 1533-1601 [Electronic] United States
• PMID: 24178578 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Review)

Chemical References

• IRS1 protein, human
• Insulin Receptor Substrate Proteins
• Mutant Proteins
• Phosphatidylinositol 3-Kinases

Topics

• Catalytic Domain
• Humans
• Insulin Receptor Substrate Proteins (genetics, metabolism)
• Molecular Targeted Therapy
• Mutant Proteins (metabolism)
• Mutation
• Neoplasms (genetics, therapy)
• Oncogenes
• Phosphatidylinositol 3-Kinases (genetics, metabolism)
• Protein Interaction Domains and Motifs (physiology)
• Signal Transduction