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Title: Structural and Functional Consequences of Three Cancer-Associated Mutations of the Oncogenic Phosphatase SHP2

Journal Article · · Biochemistry
 [1];  [2];  [1];  [1];  [3];  [2];  [2];  [2];  [2];  [2];  [2];  [2];  [1]
  1. Harvard Medical School, Boston, MA (United States); Dana-Farber Cancer Inst., Boston, MA (United States)
  2. Novartis Inst. for Biomedical Research, Cambridge, MA (United States)
  3. Frederick National Lab. for Cancer Research, Frederick, MD (United States). Leidos Biomedical Research, Inc., Basic Science Program
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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 disorders, 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 remain poorly understood. Here, in this paper, we combine X-ray crystallography, small-angle X-ray scattering, and biochemistry to elucidate structural and mechanistic features of three cancer-associated SHP2 variants harboring single point mutations within the N-SH2:PTP interdomain autoinhibitory interface. Our findings directly compare the impact of each mutation on autoinhibition of the phosphatase and advance the development of structure-guided and mutation-specific SHP2 therapies.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Organization:
Novartis-Dana Farber Cancer Institute Drug Development Program; William Lawrence-Blanche Hughes Foundation; American Cancer Society
Grant/Contract Number:
128126
OSTI ID:
1249241
Journal Information:
Biochemistry, Vol. 55, Issue 15; ISSN 0006-2960
Publisher:
American Chemical Society (ACS)Copyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 41 works
Citation information provided by
Web of Science

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Cited By (4)

Structural reorganization of SHP2 by oncogenic mutations and implications for oncoprotein resistance to allosteric inhibition journal October 2018
Mechanism of activating mutations and allosteric drug inhibition of the phosphatase SHP2 journal October 2018
De novo activating mutations drive clonal evolution and enhance clonal fitness in KMT2A-rearranged leukemia journal May 2018
Canine histiocytic sarcoma cell lines with SHP2 p.Glu76Gln or p.Glu76Ala mutations are sensitive to allosteric SHP2 inhibitor SHP099 journal August 2019

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Related Subjects

60 APPLIED LIFE SCIENCES
Cancer
Peptides and proteins
Genetics
X-ray scattering
Conformation