Structural and Functional Consequences of Three Cancer-Associated Mutations of the Oncogenic Phosphatase SHP2
Open accessAbstract
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.
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SHP2 contains two SH2 domains (N-SH2 and C-SH2) at N-terminal, a catalytic PTP domain, and two phosphorylable tyrosine residues (Tyr542 and Tyr580) at C-terminal.
“Structurally, SHP2 contains two SH2 domains (N-SH2 and C-SH2) at the N-terminal, a catalytic PTP domain, and two phosphorylable tyrosine residues (Tyr542 and Tyr580) at the C-terminal.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [260]
SHP2 is involved in regulation of multiple signaling pathways, including RAS-MAPK, PI3K-AKT and JAK-STAT.
“As protein tyrosine phosphorylation plays an essential role in multiple intracellular processes, SHP2 is involved in the regulation of multiple signaling pathways, including those involved in cancer cells, such as RAS-MAPK, PI3K-AKT and JAK-STAT pathways.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [260]
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- Authors
- LaRochelle, J. R., Fodor, M., Xu, X., Durzynska, I., Fan, L., Stams, T., Chan, H. M., LaMarche, M. J., Chopra, R., Wang, P., Fortin, P. D., Acker, M. G., & Blacklow, S. C.
- Affiliations
- Harvard University (US)
- Frederick National Laboratory for Cancer Research (US)
- Novartis Institutes for BioMedical Research (CH)
- Corresponding author
- Blacklow, Stephen C.
- ORCID
- Venue
- Biochemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2016-04-11
- Volume
- 55
- Issue
- 15
- Pages
- 2269-2277
- ISSN
- 0006-2960 (ISSN-L)
- 1520-4995
- PMC
- PMC4900891
- OpenAlex
- W2317996983
- Cited by
- 70
- References
- 38
- Citations by year
- 2026: 5 · 2025: 9 · 2024: 4 · 2023: 8 · 2022: 9 · 2021: 11 · 2020: 6 · 2019: 6 · 2018: 7 · 2017: 5
- FWCI
- 3.29
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biochemistry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
- The Novartis Repository (Novartis) (submittedVersion)
- Funders
- Novartis
- American Cancer Society (128126)
- National Institute of General Medical Sciences (P50 GM107618-01A1)
- William Lawrence and Blanche Hughes Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Keywords
- SHP2, PTPN11, cancer-associated mutations, protein tyrosine phosphatase, autoinhibition, RAS/MAPK pathway, structure-based drug design, leukemia, germline mutations, somatic mutations
- MeSH terms
- Proto-Oncogene Mas, Cell Transformation, Neoplastic, Enzyme Activation, Humans, Leukemia, Ligands, Models, Molecular, Neoplasms, Oncogenes, Structure-Activity Relationship, Point Mutation, Protein Structure, Tertiary, Crystallography, X-Ray, Amino Acid Substitution, Scattering, Small Angle, Protein Tyrosine Phosphatase, Non-Receptor Type 11
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