Regulation of PTP1B stability and signaling by the PKA scaffold protein praja2

Protein tyrosine phosphatase 1B (PTP1B) is a non-transmembrane protein implicated as negative regulator in the insulin and leptin pathways. PTP1B is also implicated in the development of breast cancer due to its dephosphorylating role on the proto-oncogene Src. During these years, PTP1B has emerged as a promising potential therapeutic target for the treatment of the type 2 diabetes. PTP1B control mechanisms are still controversial and not well understood. Here, I've contributed to identify a novel mechanism of regulation of PTP1B mediated by the ubiquitin-proteasome pathway. We identify the E3 ligase praja2 as novel interactor and regulator of PTP1B. Thus, praja2 ubiquitinates PTP1B and sustains the insulin pathway, interfering with praja2 expression or activity negatively impacts on the insulin pathway. This different control mechanism of the insulin pathway through PTP1B ubiquitination adds a new dowel to the comprehension of the molecular basis of metabolic disorders.