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Structural and functional consequences of three cancer-associated mutations of the oncogenic phosphatase SHP2

LaRochelle, Jonathan and Fodor, Michelle and Durzynska, Izabela and Xu, Xiang and Fan, Lixing and Stams, Travis and Chan, Ho Man and Lamarche, Matthew and Chopra, Rajiv and Wang, Ping and Fortin, Pascal and Acker, Michael and Blacklow, Stephen (2016) Structural and functional consequences of three cancer-associated mutations of the oncogenic phosphatase SHP2. Biochemistry, 55 (15). pp. 2269-2277. ISSN 1520-4995

Abstract

The proto-oncogene PTPN11 encodes a cytoplasmic protein tyrosine phosphatase, SHP2, which is required for normal development and sustained activation of the Ras-MAPK signaling pathway. Germline mutations in SHP2 cause developmental disor- ders, and somatic mutations have been identified in childhood and adult cancers and drive leukemia in mice. Despite our knowledge of the PTPN11 variations associated with pathology, the structural and functional consequences of many disease-associated mutants re- main poorly understood. Here, we combine X-ray crystallography, small angle X-ray scattering and biochemistry to elucidate structural and mechanistic features of three SHP2 cancer variants harboring single point mutations about the N-SH2:PTP interdomain autoinhib- itory interface. Our findings directly compare the impact of each mutation on autoinhibition of the phosphatase and advance the under- standing of structure-guided and mutation-specific SHP2 therapies.

Item Type: Article
Date Deposited: 26 Apr 2016 23:45
Last Modified: 26 Apr 2016 23:45
URI: https://oak.novartis.com/id/eprint/27344

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