ArticleNature communications2025
Deep mutational scanning of the multi-domain phosphatase SHP2 reveals mechanisms of regulation and pathogenicity.
Article in Nature communications, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed.
- Clinically observed RASA1 missense mutants exhibit diverse RasGAP protein behaviors in vitro.The Journal of biological chemistry · 2026Article
- Dual functional genomics reveals a broad and convergent landscape of asciminib resistance in BCR::ABL1.Genome medicine · 2026Article
- Multiplexed single-cell transcriptomics reveals diverse phenotypic outcomes for pathogenic SHP2 variants.Science advances · 2026Article
- Functional dissection ofProceedings of the National Academy of Sciences of the United States of America · 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
- Determining the intra-residue correlation of missense variant impact using MAVE scores: implications for the ACMG/AMP PM5 criterion for DNA variant classification.Genome medicine · 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
- A hotspot phosphorylation site on SHP2 drives oncoprotein activation and drug resistance.Nature communications · 2026Article
- Proximity-labeling proteomics reveals remodeled interactomes and altered localization of pathogenic SHP2 variants.EMBO reports · 2026Article
- Loop dynamics, allostery, and function in protein tyrosine phosphatases: insights from molecular simulations.Biochemical Society transactions · 2026Review
- Data Mining for Identification of Targets and Repurposed Drugs to Eliminate Persistent Chronic Myeloid Leukaemia Stem Cells: Targeting RAS/RAF Signalling.Oncology research · 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
- Clinically observedbioRxiv : the preprint server for biology · 2025Article
- The pathogenic E139D mutation stabilizes a non-canonical active state of the multi-domain phosphatase SHP2.bioRxiv : the preprint server for biology · 2025Article
- Orchestrating function: Concerted dynamics, allostery, and catalysis in protein tyrosine phosphatases.Current opinion in structural biology · 2025Review
- Prevalence of loss-of-function, gain-of-function and dominant-negative mechanisms across genetic disease phenotypes.Nature communications · 2025Article
- A Hotspot Phosphorylation Site on SHP2 Drives Oncoprotein Activation and Drug Resistance.Research square · 2025Article
- A Hotspot Phosphorylation Site on SHP2 Drives Oncoprotein Activation and Drug Resistance.bioRxiv : the preprint server for biology · 2025Article
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Abstract
Multi-domain signaling enzymes are often regulated through extensive inter-domain interactions, and disruption of inter-domain interfaces by mutations can lead to aberrant signaling and diseases. For example, the tyrosine phosphatase SHP2 contains two phosphotyrosine recognition domains that auto-inhibit its catalytic domain. SHP2 is canonically activated by binding of these non-catalytic domains to phosphoproteins, which destabilizes its auto-inhibited state, and several mutations at the main auto-inhibitory interface have been shown to hyperactivate SHP2 in cancers and developmental disorders. Hundreds of clinically observed mutations in SHP2 have not been characterized, but their locations suggest alternative modes of dysregulation. Here, we perform deep mutational scanning on full-length SHP2 and the isolated phosphatase domain to dissect mechanisms of dysregulation. Our analysis reveals mechanistically diverse mutational effects and identifies key intra- and inter-domain interactions that contribute to SHP2 activity, dynamics, and regulation. Our datasets also provide insights into the potential pathogenicity of previously uncharacterized clinical variants.
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