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Multiplexed single-cell transcriptomics reveals diverse phenotypic outcomes for pathogenic SHP2 variants
Anne E van Vlimmeren1,2, Ross M Giglio3,4, Ziyuan Jiang1
1Department of Chemistry, Columbia University, New York, NY 10027.
Biorxiv : the Preprint Server for Biology
|July 9, 2025
Summary
Mutations in the SHP2 phosphatase gene (PTPN11) cause developmental disorders and cancer. Diverse mutations can lead to similar cell states, revealing complex links between SHP2 structure, signaling, and disease.
Area of Science:
- Molecular Biology
- Genetics
- Cell Biology
Background:
- SHP2 phosphatase, encoded by PTPN11, regulates Ras/MAPK signaling downstream of transmembrane receptors.
- PTPN11 mutations are linked to Noonan Syndrome and various cancers, with varied effects on SHP2 activity and interactions.
- Understanding how distinct mutations dysregulate SHP2 is crucial for disease comprehension.
Purpose of the Study:
- To elucidate the molecular mechanisms by which diverse PTPN11 mutations perturb SHP2 function and signaling.
- To correlate structural changes in SHP2 variants with cellular and gene expression phenotypes.
- To establish a framework linking SHP2 structural alterations to disease outcomes.
Main Methods:
- Single-cell transcriptional profiling of cells expressing various SHP2 variants.
- Protein biochemistry and structural analysis of SHP2 variants.
- Cell biology assays to assess signaling and cellular phenotypes.
Main Results:
- Loss of SHP2 catalytic activity does not fully replicate SHP2 knock-out gene expression profiles.
- Mechanistically different SHP2 mutations can converge to produce similar cellular phenotypes.
- Distinct mutations at the same residue can result in divergent cellular states.
Conclusions:
- SHP2-driven diseases are complex, with mutations having varied effects beyond simple catalytic activity.
- Convergent and divergent cellular outcomes arise from distinct SHP2 mutations.
- This study provides a framework for understanding SHP2 mutation impact on cellular function and human disease.
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