Phase Separation of Disease-Associated SHP2 Mutants Underlies MAPK Hyperactivation
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The non-receptor protein tyrosine phosphatase (PTP) SHP2, encoded by PTPN11, plays an essential role in RAS-mitogen-activated protein kinase (MAPK) signaling during normal development. It has been perplexing as to why both enzymatically activating and inactivating mutations in PTPN11 result in human developmental disorders with overlapping clinical manifestations. Here, we uncover a common liquid-liquid phase separation (LLPS) behavior shared by these disease-associated SHP2 mutants. SHP2 LLPS is mediated by the conserved well-folded PTP domain through multivalent electrostatic interactions and regulated by an intrinsic autoinhibitory mechanism through conformational changes. SHP2 allosteric inhibitors can attenuate LLPS of SHP2 mutants, which boosts SHP2 PTP activity. Moreover, disease-associated SHP2 mutants can recruit and activate wild-type (WT) SHP2 in LLPS to promote MAPK activation. These results not only suggest that LLPS serves as a gain-of-function mechanism involved in the pathogenesis of SHP2-associated human diseases but also provide evidence that PTP may be regulated by LLPS that can be therapeutically targeted.
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SHP099 and ET070 correct hyperactivation of mutant SHP2 by stabilizing its closed conformation.
“Simple synthetic compounds can also function as intramolecular glues, as shown by SHP099 110,111 and ET070 (Fig. 6), 112 which correct the hyperactivation of mutant SHP2 by stabilizing its closed conformation.”
From Chasing molecular glue degraders: screening approaches (2022) · cites this paper as [112]
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- Authors
- Zhu, G., Xie, J., Kong, W., Xie, J., Li, Y., Du, L., Zheng, Q., Sun, L., Guan, M., Li, H., Zhu, T., He, H., Liu, Z., Xia, X., Kan, C., Tao, Y., Shen, H. C., Li, D., Wang, S., Yu, Y., Yu, Z.-H., Zhang, Z.-Y., Liu, C., & Zhu, J.
- Affiliations
- Chinese Academy of Sciences (CN)
- Shanghai Jiao Tong University (CN)
- Anhui Medical University (CN)
- Roche (China) (CN)
- Purdue University West Lafayette (US)
- Corresponding author
- Liu, Cong
- Zhu, Jidong
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2020-10
- Volume
- 183
- Issue
- 2
- Pages
- 490-502.e18
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC7572904
- OpenAlex
- W3089746615
- Cited by
- 267
- References
- 53
- Citations by year
- 2026: 31 · 2025: 56 · 2024: 61 · 2023: 48 · 2022: 46 · 2021: 23 · 2020: 1
- FWCI
- 9.57
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- Science and Technology Commission of Shanghai Municipality
- National Natural Science Foundation of China
- 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 › RNA Research and Splicing
- Keywords
- SHP2, PTPN11, liquid-liquid phase separation, protein tyrosine phosphatase, MAPK signaling, RAS/MAPK pathway, disease-associated mutations, gain-of-function mechanism, allosteric inhibitors, autoinhibition, developmental disorders, therapeutic targeting
- MeSH terms
- Mouse Embryonic Stem Cells, A549 Cells, Gain of Function Mutation, Animals, Child, Child, Preschool, Female, Humans, Male, Mutation, Signal Transduction, src Homology Domains, Mitogen-Activated Protein Kinases, MAP Kinase Signaling System, Mice, Protein Tyrosine Phosphatase, Non-Receptor Type 11, HEK293 Cells, Human Umbilical Vein Endothelial Cells
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