Tyrosine phosphatases are important signaling enzymes that help regulate the phosphorylation states of proteins. Their function is critical to cell communication, proliferation, and migration. Impaired activity of these enzymes can cause altered levels of tyrosine phosphorylation, which can lead to human disease. Protein tyrosine phosphatase 1B (PTP1B) is most well-known for its role in the insulin and leptin receptor pathways, making it an attractive target for the treatment of type II diabetes and obesity. PTP1B has been shown to interact with the adaptor protein Grb2, which is a critical mediator between cell membrane-bound growth factor receptors and the Ras signaling pathway. Grb2 also interacts with insulin receptor substrate 1, a known substrate of PTP1B. We have confirmed the interaction between PTP1B and Grb2, which is driven in part by the proline-rich region of PTP1B. Additionally, we have shown that Grb2 binding to PTP1B causes an increase in its catalytic activity. Interestingly, this effect does not appear to be dependent on the proline-rich region of PTP1B, which may suggest a secondary contact region between the two proteins. Finally, we are using biophysical techniques such as NMR and HDX-MS to further characterize this interaction, in order to determine the molecular basis for the effect of Grb2 binding on PTP1B activity. A better understanding of this interaction will reveal new insights into PTP1B and Grb2 signaling biology.

Biophysical insights into the regulation of the tyrosine phosphatase PTP1B by the adaptor protein Grb2

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