ArticleCellular and molecular life sciences : CMLS2023
SHP2 clinical phenotype, cancer, or RASopathies, can be predicted by mutant conformational propensities.
Article in Cellular and molecular life sciences : CMLS, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 25 citations in OpenAlex.
- From static structures to dynamic energy landscapes: the latest revolution in molecular biology.Current opinion in structural biology · 2026Review
- DeepPath: overcoming data scarcity for protein transition pathway prediction using physics-based deep learning.Chemical science · 2026Article
- Allostery in Biomolecular Condensates.Journal of molecular biology · 2026Review
- Oncogenic PI3Kα variants reveal graded conformational spectrum with mutation-specific cryptic pockets.Communications chemistry · 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
- Oncogenic PI3Kα variants reveal graded conformational spectrum with mutation-specific cryptic pockets.bioRxiv : the preprint server for biology · 2025Article
- Article
- The pathogenic E139D mutation stabilizes a non-canonical active state of the multi-domain phosphatase SHP2.bioRxiv : the preprint server for biology · 2025Article
- Mutations in tumor signaling, metastases, and synthetic lethality establish distinct patterns.PLoS computational biology · 2025Article
- Tumors and their microenvironments: Learning from pediatric brain pathologies.Biochimica et biophysica acta. Reviews on cancer · 2025Review
- Pioneer in Molecular Biology: Conformational Ensembles in Molecular Recognition, Allostery, and Cell Function.Journal of molecular biology · 2025Review
- Computational studies on the functional and structural impact of pathogenic mutations in enzymes.Protein science : a publication of the Protein Society · 2025Review
- Molecular principles underlying aggressive cancers.Signal transduction and targeted therapy · 2025Review
- Allosteric modulation of NF1 GAP: Differential distributions of catalytically competent populations in loss-of-function and gain-of-function mutants.Protein science : a publication of the Protein Society · 2025Article
- mTOR Variants Activation Discovers PI3K-like Cryptic Pocket, Expanding Allosteric, Mutant-Selective Inhibitor Designs.Journal of chemical information and modeling · 2025Article
- M-Ras distinct activation scenarios: A mechanistic outlook and targeting.Computational and structural biotechnology journal · 2025Article
- Case Report: Genomic characterization of a rare skull-base plasmacytoma.Frontiers in oncology · 2025Article
- Paternal age, de novo mutations, and offspring health? New directions for an ageing problem.Human reproduction (Oxford, England) · 2024Review
- Ras, RhoA, and vascular pharmacology in neurodevelopment and aging.Neurochemistry international · 2024Review
- The value of protein allostery in rational anticancer drug design: an update.Expert opinion on drug discovery · 2024Review
Corrections and comments
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Authors and funding
4 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
SHP2 phosphatase promotes full activation of the RTK-dependent Ras/MAPK pathway. Its mutations can drive cancer and RASopathies, a group of neurodevelopmental disorders (NDDs). Here we ask how same residue mutations in SHP2 can lead to both cancer and NDD phenotypes, and whether we can predict what the outcome will be. We collected and analyzed mutation data from the literature and cancer databases and performed molecular dynamics simulations of SHP2 mutants. We show that both cancer and Noonan syndrome (NS, a RASopathy) mutations favor catalysis-prone conformations. As to cancer versus RASopathies, we demonstrate that cancer mutations are more likely to accelerate SHP2 activation than the NS mutations at the same genomic loci, in line with NMR data for K-Ras4B more aggressive mutations. The compiled experimental data and dynamic features of SHP2 mutants lead us to propose that different from strong oncogenic mutations, SHP2 activation by NS mutations is less likely to induce a transition of the ensemble from the SHP2 inactive state to the active state. Strong signaling promotes cell proliferation, a hallmark of cancer. Weak, or moderate signals are associated with differentiation. In embryonic neural cells, dysregulated differentiation is connected to NDDs. Our innovative work offers structural guidelines for identifying and correlating mutations with clinical outcomes, and an explanation for why bearers of RASopathy mutations may have a higher probability of cancer. Finally, we propose a drug strategy against SHP2 variants-promoting cancer and RASopathies.
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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.