Mechanistic insights explain the transforming potential of the T507K substitution in the protein-tyrosine phosphatase SHP2
Open accessAbstract
gene have been linked to many different types of human diseases, including developmental disorders, leukemia, and solid tumors. Unlike most SHP2-activating mutations, the T507K substitution in SHP2 is unique in that it exhibits oncogenic Ras-like transforming activity. However, the biochemical basis of how the SHP2/T507K variant elicits transformation remains unclear. By combining kinetic and biophysical methods, X-ray crystallography, and molecular modeling, as well as using cell biology approaches, here we uncovered that the T507K substitution alters both SHP2 substrate specificity and its allosteric regulatory mechanism. We found that although SHP2/T507K exists in the closed, autoinhibited conformation similar to the WT enzyme, the interactions between its N-SH2 and protein-tyrosine phosphatase domains are weakened such that SHP2/T507K possesses a higher affinity for the scaffolding protein Grb2-associated binding protein 1 (Gab1). We also discovered that the T507K substitution alters the structure of the SHP2 active site, resulting in a change in SHP2 substrate preference for Sprouty1, a known negative regulator of Ras signaling and a potential tumor suppressor. Our results suggest that SHP2/T507K's shift in substrate specificity coupled with its preferential association of SHP2/T507K with Gab1 enable the mutant SHP2 to more efficiently dephosphorylate Sprouty1 at pTyr-53. This dephosphorylation hyperactivates Ras signaling, which is likely responsible for SHP2/T507K's Ras-like transforming activity.
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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 [264]
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- Authors
- Zhang, R.-Y., Yu, Z.-H., Chen, L., Walls, C. D., Zhang, S., Wu, L., & Zhang, Z.-Y.
- Affiliations
- Purdue University West Lafayette (US)
- Corresponding author
- Zhang, Zhong-Yin
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2020-05
- Volume
- 295
- Issue
- 18
- Pages
- 6187-6201
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC7196634
- OpenAlex
- W3012220809
- Cited by
- 22
- References
- 51
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 1 · 2023: 4 · 2022: 6 · 2021: 2
- FWCI
- 0.97
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
- Funders
- HHS | National Institutes of Health (RO1 CA069202, RO1 CA207288)
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- SHP2, substrate specificity, allosteric regulation, autoinhibition, SH2 domain, Gab1, Sprouty1, Ras signaling, dephosphorylation, tumor suppressor
- MeSH terms
- Amino Acid Sequence, Humans, Models, Molecular, Crystallography, X-Ray, Amino Acid Substitution, Catalytic Domain, Protein Tyrosine Phosphatase, Non-Receptor Type 11
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