The identification of substrates for protein tyrosine phosphatases (PTPs) is critical for a complete understanding of how these enzymes function. In a recent study in the JBC, Bonhamet al. developed a modified method combining substrate-trapping mutations with proximity-labeling MS to identify the protein substrates and interactors of PTP1B. This method revealed interaction networks in breast cancer cell models and discovered novel targets of PTP1B that regulate HER2 signaling pathways. This strategy represents a versatile new tool for identifying the functional interactions between PTPs and their substrates.