Regulation of protein tyrosine phosphatase 1B by sumoylation

Abstract

Protein-tyrosine phosphatase 1B (PTP1B) is an ubiquitously expressed enzyme that negatively regulates growth-factor signalling and cell proliferation by binding to and dephosphorylating key receptor tyrosine kinases, such as the insulin receptor. It is unclear how the activity of PTP1B is regulated. Using a yeast two-hybrid assay, a protein inhibitor of activated STAT1 (PIAS1) was isolated as a PTP1B-interacting protein. Here, we show that PIAS1, which functions as a small ubiquitin-like modifier (SUMO) E3 ligase, associates with PTP1B in mammalian fibroblasts and catalyses sumoylation of PTP1B. Sumoylation of PTP1B reduces its catalytic activity and inhibits the negative effect of PTP1B on insulin receptor signalling and on transformation by the oncogene v-crk. Insulin-stimulated sumoylation of endogenous PTP1B results in a transient downregulation of the enzyme; this event does not occur when the endogenous enzyme is replaced with a sumoylation-resistant mutant of PTP1B. These results suggest that sumoylation, which has been implicated primarily in processes in the nucleus and nuclear pore, also modulates a key enzyme-substrate signalling complex that regulates metabolism and cell proliferation.

Interplay between Sumoylation and Phosphorylation for Protection against α-Synuclein Inclusions

“…Sumoylation can modulate the specific interaction with kinases or phosphatases by changing substrate surfaces and activity. In particular, sumoylation of protein-tyrosine phosphatase 1B has been shown to reduce catalytic activity and therefore change the phosphorylation status of substrates (76).…”

SENP1 regulates IFN-γ−STAT1 signaling through STAT3−SOCS3 negative feedback loop

“…Here, we show a previously unexplored aspect of SENP1 function in the regulation of macrophage activation by targeting a phosphatase PTP1B. SUMOylation represses the de-phosphorylation activity of PTP1B and inhibits the negative effect of PTP1B on insulin receptor signaling as well as transformation by the oncogene v-crk (Dadke et al, 2007). This study shows that SUMOylation of PTP1B can reduce its inhibition to STAT3 in IFN-γ signaling.…”

“…We observed an accumulation of SUMOylated PTP1B protein in Senp1−/− but not in Senp1+/+ cells ( Figure 3A), indicating that SENP1 functions as a specific de-SUMOylation protease for PTP1B. SUMOylated PTP1B impairs its intrinsic phosphatase activity (Dadke et al, 2007). We treated cells with PTP1B-specific inhibitor, and found that PTP1B inhibition augmented STAT3 phosphorylation but reduced STAT1 activation, which mimicked the response of SENP1-deficient macrophages to IFN-γ signal ( Figure 3B).…”

“…As shown in Supplementary Figure S8, IFN-γ-induced STAT3 phosphorylation was significantly increased in PTP1B-specific inhibitor-treated macrophages but not in TCPTP inhibitortreated samples, indicating that PTP1B is a tyrosine phosphatase in response to STAT3 de-phosphorylation in macrophages. Previous studies have reported that PTP1B is a SUMOylated protein (Dadke et al, 2007). To reveal whether PTP1B is a SENP1 target in STAT3 regulation, we analyzed PTP1B SUMOylation status in Senp1−/− cells in comparison with Senp1+/+ cells.…”

Nouvelles fonctions extranucléaires de la sumoylation des protéines dans le système nerveux central

“…Elle est en outre impliquée dans la régulation de la signalisation de l'insuline via son activité de phosphatase sur de nombreux récep-teurs à activité tyrosine kinase. La sumoylation de PTP1B en réponse à l'insuline diminue à la fois l'activité et l'expression de PTP1B [13]. Ce mécanisme pourrait participer au contrôle neuronal de la prise alimentaire.…”