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Updated: Mar 23, 2026
Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors
Published on: July 17, 2020
Structural and Functional Consequences of Three Cancer-Associated Mutations of the Oncogenic Phosphatase SHP2
Jonathan R LaRochelle1,2, Michelle Fodor, Xiang Xu1,2
1Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School , Boston, Massachusetts 02115, United States.
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 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, 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.
Insights
Mutations in the PTPN11 gene, which encodes SHP2 phosphatase, cause developmental disorders and cancer. This study reveals how specific PTPN11 mutations disrupt SHP2
Area of Science:
- Biochemistry
- Structural Biology
- Oncology
Background:
- The PTPN11 gene encodes SHP2, a protein tyrosine phosphatase crucial for development and Ras-MAPK signaling.
- Germline and somatic PTPN11 mutations are linked to developmental disorders and various cancers, including leukemia.
- The precise structural and functional impacts of many disease-associated SHP2 mutations are not well understood.
Purpose of the Study:
- To investigate the structural and mechanistic consequences of three cancer-associated SHP2 variants.
- To elucidate the impact of mutations on the autoinhibitory interface of SHP2.
- To provide insights for developing targeted SHP2 therapies.
Main Methods:
- X-ray crystallography
- Small-angle X-ray scattering (SAXS)
- Biochemical assays
Main Results:
- Detailed structural and mechanistic characterization of three cancer-associated SHP2 mutants.
- Demonstrated how specific mutations affect the autoinhibition of SHP2 phosphatase activity.
- Provided a comparative analysis of the impact of distinct mutations at the N-SH2:PTP interface.
Conclusions:
- The study elucidates the molecular mechanisms underlying disease-associated SHP2 mutations.
- Findings advance the understanding of SHP2 regulation and its role in cancer.
- Results support the development of structure-guided, mutation-specific therapies targeting SHP2.
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