Gain of interaction with IRS1 by p110?-helical domain mutants is crucial for their oncogenic functions.

Hao, Yujun, Wang, Chao, Cao, Bo, Hirsch, Brett M, Song, Jing, Markowitz, Sanford D., Ewing, Rob M., Sedwick, David, Liu, Lili, Zheng, Weiping and Wang, Zhenghe (2013) Gain of interaction with IRS1 by p110?-helical domain mutants is crucial for their oncogenic functions. Cancer Cell, 23 (5), 583-593. (doi:10.1016/j.ccr.2013.03.021). (PMID:23643389)

Abstract

PIK3CA, which encodes the p110? catalytic subunit of phosphatidylinositol 3-kinase ?, 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 p110? E545K, but not p110? H1047R, gains the ability to associate with IRS1 independent of the p85 regulatory subunit, thereby rewiring this oncogenic signaling pathway. Disruption of the IRS1-p110? E545K interaction destabilizes the p110? protein, reduces AKT phosphorylation, and slows xenograft tumor growth of a cancer cell line expressing p110? E545K. Moreover, a hydrocarbon-stapled peptide that disrupts this interaction inhibits the growth of tumors expressing p110? E545K.

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Contributors

Author: Rob M. Ewing

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