Structural and Functional Consequences of Three Cancer-Associated Mutations of the Oncogenic Phosphatase SHP2
- Harvard Medical School, Boston, MA (United States); Dana-Farber Cancer Inst., Boston, MA (United States)
- Novartis Inst. for Biomedical Research, Cambridge, MA (United States)
- Frederick National Lab. for Cancer Research, Frederick, MD (United States). Leidos Biomedical Research, Inc., Basic Science Program
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
Web of Science
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 |
Similar Records
Dual Allosteric Inhibition of SHP2 Phosphatase
Mechanistic insights explain the transforming potential of the T507K substitution in the protein-tyrosine phosphatase SHP2