Department of Genetics and Genome Sciences, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, USA.
Cancer Cell. 2013 May 13;23(5):583-93. doi: 10.1016/j.ccr.2013.03.021. Epub 2013 May 2.
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.
PIK3CA 编码磷脂酰肌醇 3-激酶 α 的 p110α 催化亚基，在人类癌症中经常发生突变。这些突变大多数发生在两个热点：位于螺旋区和激酶区的 E545K 和 H1047R。在这里，我们报告 p110α E545K 但不是 p110α H1047R 获得了与 IRS1 结合的能力，而无需 p85 调节亚基，从而重新布线这种致癌信号通路。IRS1-p110α E545K 相互作用的破坏会使 p110α 蛋白不稳定，降低 AKT 磷酸化，并减缓表达 p110α E545K 的癌细胞系的异种移植物肿瘤生长。此外，破坏这种相互作用的碳氢化合物订书肽抑制表达 p110α E545K 的肿瘤的生长。
