title: 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.
authors.affiliation: Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA.
authors.forename: Shrikrishna
authors.initials: S
authors.lastname: Dadke
authors.forename: Sophie
authors.initials: S
authors.lastname: Cotteret
authors.forename: Shu-Chin
authors.initials: SC
authors.lastname: Yip
authors.forename: Zahara M
authors.initials: ZM
authors.lastname: Jaffer
authors.forename: Fawaz
authors.initials: F
authors.lastname: Haj
authors.forename: Alexey
authors.initials: A
authors.lastname: Ivanov
authors.forename: Frank
authors.initials: F
authors.lastname: Rauscher
authors.forename: Ke
authors.initials: K
authors.lastname: Shuai
authors.forename: Tony
authors.initials: T
authors.lastname: Ng
authors.forename: Benjamin G
authors.initials: BG
authors.lastname: Neel
authors.forename: Jonathan
authors.initials: J
authors.lastname: Chernoff
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D015971:Gene Expression Regulation, Enzymologic; D051379:Mice; D036641:Microscopy, Fluorescence, Multiphoton / Q000379:methods; D050828:Protein Inhibitors of Activated STAT / Q000302:isolation & purification / Q000378:metabolism*; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000235:genetics* / Q000378:metabolism; D025842:SUMO-1 Protein / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection
chemical_list: D050828:Protein Inhibitors of Activated STAT; D025842:SUMO-1 Protein; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases; C516609:Ptpn1 protein, mouse