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Updated: Jan 8, 2026
Characterization of Neuronal Lysosome Interactome with Proximity Labeling Proteomics
Published on: June 23, 2022
Proximity-labeling proteomics reveals remodeled interactomes and altered localization of pathogenic SHP2 variants
Anne E van Vlimmeren1,2, Lauren C Tang2, Ziyuan Jiang1
1Department of Chemistry, Columbia University, New York, NY, 10027, USA.
Abstract:
Missense mutations in PTPN11, which encodes the protein tyrosine phosphatase SHP2, are common in several developmental disorders and cancers. While many mutations disrupt auto-inhibition and hyperactivate SHP2, several do not enhance catalytic activity. Both activating and non-activating mutations could potentially drive pathogenic signaling by altering SHP2 interactions or localization. We employed proximity-labeling proteomics to map the interaction networks of wild-type SHP2, ten clinically relevant mutants, and SHP2 bound to an inhibitor that stabilizes its auto-inhibited state. Our analyses reveal mutation- and inhibitor-dependent alterations in the SHP2 interactome, with several mutations also changing localization. Some mutants show increased mitochondrial localization and impact mitochondrial function. This study provides a resource for exploring SHP2 signaling and offers new insights into the molecular basis of SHP2-driven diseases. Furthermore, this work highlights the capacity for proximity-labeling proteomics to detect missense-mutation-dependent changes in protein interactions and localization.
Insights
Missense mutations in protein tyrosine phosphatase SHP2 (PTPN11) can cause developmental disorders and cancers. This study used proteomics to reveal how these mutations alter SHP2 interactions and localization, impacting cellular functions.
Area of Science:
- Biochemistry
- Molecular Biology
- Genetics
Background:
- Missense mutations in PTPN11, encoding SHP2, are linked to developmental disorders and cancers.
- While some mutations hyperactivate SHP2, others do not affect its catalytic activity, suggesting alternative pathogenic mechanisms.
Purpose of the Study:
- To map the interaction networks and localization of wild-type SHP2, clinically relevant mutants, and inhibitor-bound SHP2.
- To understand how missense mutations affect SHP2's molecular interactions and cellular localization.
Main Methods:
- Proximity-labeling proteomics was employed to analyze SHP2 interactomes.
- Wild-type SHP2, ten mutants, and inhibitor-bound SHP2 were studied.
Main Results:
- Mutation- and inhibitor-dependent alterations in the SHP2 interactome were identified.
- Several mutations altered SHP2 localization, with some mutants showing increased mitochondrial localization and impacting mitochondrial function.
Conclusions:
- This study provides a valuable resource for understanding SHP2 signaling in disease.
- Proximity-labeling proteomics can effectively detect mutation-dependent changes in protein interactions and localization, offering insights into SHP2-driven diseases.
