Proximity-labeling proteomics reveals remodeled interactomes and altered localization of pathogenic SHP2 variants

TL;DR

This study uses a technique called proximity-labeling proteomics to show how mutations in the SHP2 protein affect its interactions and location in cells, especially in mitochondria, which could explain how these mutations cause disease.

Contribution

The study reveals mutation-specific and inhibitor-specific changes in SHP2's protein interactions and mitochondrial localization using proximity-labeling proteomics.

Findings

SHP2 mutations alter its interaction network and subcellular localization in a mutation- and inhibitor-dependent manner.

Some SHP2 mutants show increased mitochondrial localization and interact with components of the electron transport chain.

Proximity-labeling proteomics identifies a core SHP2 interactome shared across disease variants, including mitochondrial proteins.

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.

Proximity-labeling proteomics maps how disease-associated mutations in the tyrosine phosphatase SHP2 alter its interaction network and subcellular localization, revealing mutation- and inhibitor-specific effects on cellular signaling and mitochondrial function. These findings provide new insights into SHP2-driven diseases and illustrate the utility of proximity-labeling proteomics for dissecting mutation-dependent protein network changes.

Proximity-labeling proteomics reveals that mechanistically distinct disease-associated mutations in SHP2 cause different changes to the SHP2 protein interaction network.Proximity-labeling proteomics identifies a core SHP2 interactome in HEK 293 cells, shared across several disease variants, which includes many mitochondrial proteins.Several SHP2 mutations enhanced mitochondrial localization and interactions with components of the electron transport chain.

Proximity-labeling proteomics reveals that mechanistically distinct disease-associated mutations in SHP2 cause different changes to the SHP2 protein interaction network.

Proximity-labeling proteomics identifies a core SHP2 interactome in HEK 293 cells, shared across several disease variants, which includes many mitochondrial proteins.

Several SHP2 mutations enhanced mitochondrial localization and interactions with components of the electron transport chain.

Proximity-labeling proteomics of the tyrosine phosphatase SHP2 reveal how disease-associated mutations alter its interaction network and subcellular localization.

Figures