ArticleThe Journal of biological chemistry
A novel partially open state of SHP2 points to a "multiple gear" regulation mechanism.
Article in The Journal of biological chemistry. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 31 citations in OpenAlex.
- DeepPath: overcoming data scarcity for protein transition pathway prediction using physics-based deep learning.Chemical science · 2026Article
- High-throughput biochemical phenotyping of SHP2 variants reveals the molecular basis of diseases and allosteric drug inhibition.bioRxiv : the preprint server for biology · 2026Article
- Cancer-Causing Mutations Alter the Interplay Between Loop Dynamics and Catalysis in the Protein Tyrosine Phosphatases SHP-1 and SHP-2.bioRxiv : the preprint server for biology · 2026Article
- The pathogenic E139D mutation stabilizes a non-canonical active state of the multi-domain phosphatase SHP2.Protein science : a publication of the Protein Society · 2025Article
- The pathogenic E139D mutation stabilizes a non-canonical active state of the multi-domain phosphatase SHP2.bioRxiv : the preprint server for biology · 2025Article
- Deep mutational scanning of the multi-domain phosphatase SHP2 reveals mechanisms of regulation and pathogenicity.Nature communications · 2025Article
- Targeting SHP2 Cryptic Allosteric Sites for Effective Cancer Therapy.International journal of molecular sciences · 2024Article
- Complex Roles ofAnnual review of cancer biology · 2024Article
- SHP2 regulates GluA2 tyrosine phosphorylation required for AMPA receptor endocytosis and mGluR-LTD.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Single Ion Pair Is Essential for Stabilizing SHP2's Open Conformation.Biochemistry · 2024Article
- Allosteric SHP2 inhibition increases apoptotic dependency on BCL2 and synergizes with venetoclax in FLT3- and KIT-mutant AML.Cell reports. Medicine · 2023Article
- Review
- Quantitation of autoinhibitory defects in pathogenic SHP2 mutants by differential scanning fluorimetry.Analytical biochemistry · 2023Article
- Targeting protein phosphatases in cancer immunotherapy and autoimmune disorders.Nature reviews. Drug discovery · 2023Review
- SHP2 deneddylation mediates tumor immunosuppression in colon cancer via the CD47/SIRPα axis.The Journal of clinical investigation · 2023Article
- Article
- The Tyrosine Phosphatase SHP2: A New Target for Insulin Resistance?Biomedicines · 2022Review
- Non-ergodicity of a globular protein extending beyond its functional timescale.Chemical science · 2022Article
- Modeling (not so) rare developmental disorders associated with mutations in the protein-tyrosine phosphatase SHP2.Frontiers in cell and developmental biology · 2022Review
- Cx43 Promotes Endothelial Cell Migration and Angiogenesis via the Tyrosine Phosphatase SHP-2.International journal of molecular sciences · 2021Article
Corrections and comments
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Authors and funding
23 authors at 7 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The protein tyrosine phosphatase SHP2 mediates multiple signal transductions in various cellular pathways, controlled by a variety of upstream inputs. SHP2 dysregulation is causative of different types of cancers and developmental disorders, making it a promising drug target. However, how SHP2 is modulated by its different regulators remains largely unknown. Here, we use single-molecule fluorescence resonance energy transfer and molecular dynamics simulations to investigate this question. We identify a partially open, semiactive conformation of SHP2 that is intermediate between the known open and closed states. We further demonstrate a "multiple gear" regulatory mechanism, in which different activators (e.g., insulin receptor substrate-1 and CagA), oncogenic mutations (e.g., E76A), and allosteric inhibitors (e.g., SHP099) can shift the equilibrium of the three conformational states and regulate SHP2 activity to different levels. Our work reveals the essential role of the intermediate state in fine-tuning the activity of SHP2, which may provide new opportunities for drug development for relevant cancers.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.