title: The R3 receptor-like protein tyrosine phosphatase subfamily inhibits insulin signalling by dephosphorylating the insulin receptor at specific sites.
abstract: The autophosphorylation of specific tyrosine residues occurs in the cytoplasmic region of the insulin receptor (IR) upon insulin binding, and this in turn initiates signal transduction. The R3 subfamily (Ptprb, Ptprh, Ptprj and Ptpro) of receptor-like protein tyrosine phosphatases (RPTPs) is characterized by an extracellular region with 6-17 fibronectin type III-like repeats and a cytoplasmic region with a single phosphatase domain. We herein identified the IR as a substrate for R3 RPTPs by using the substrate-trapping mutants of R3 RPTPs. The co-expression of R3 RPTPs with the IR in HEK293T cells suppressed insulin-induced tyrosine phosphorylation of the IR. In vitro assays using synthetic phosphopeptides revealed that R3 RPTPs preferentially dephosphorylated a particular phosphorylation site of the IR: Y960 in the juxtamembrane region and Y1146 in the activation loop. Among four R3 members, only Ptprj was co-expressed with the IR in major insulin target tissues, such as the skeletal muscle, liver and adipose tissue. Importantly, the activation of IR and Akt by insulin was enhanced, and glucose and insulin tolerance was improved in Ptprj-deficient mice. These results demonstrated Ptprj as a physiological enzyme that attenuates insulin signalling in vivo, and indicate that an inhibitor of Ptprj may be an insulin-sensitizing agent.
authors.affiliation: Division of Molecular Neurobiology, Department of Neurobiology, National Institute for Basic Biology, Okazaki 444-8787, Japan; Department of Basic Biology, School of Life Science, The Graduate University for Advanced Studies (SOKENDAI), Okazaki 444-8787, Japan;
authors.forename: Takafumi
authors.initials: T
authors.lastname: Shintani
authors.affiliation: Division of Molecular Neurobiology, Department of Neurobiology, National Institute for Basic Biology, Okazaki 444-8787, Japan; Department of Basic Biology, School of Life Science, The Graduate University for Advanced Studies (SOKENDAI), Okazaki 444-8787, Japan;
authors.forename: Satoru
authors.initials: S
authors.lastname: Higashi
authors.affiliation: Division of Molecular Neurobiology, Department of Neurobiology, National Institute for Basic Biology, Okazaki 444-8787, Japan;
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Takeuchi
authors.affiliation: Dipartimento di Medicina Sperimentale e Clinica, University Magna Græcia, Campus "S. Venuta", Catanzaro 88100, Italy; and.
authors.forename: Eugenio
authors.initials: E
authors.lastname: Gaudio
authors.affiliation: Dipartimento di Medicina Sperimentale e Clinica, University Magna Græcia, Campus "S. Venuta", Catanzaro 88100, Italy; and.
authors.forename: Francesco
authors.initials: F
authors.lastname: Trapasso
authors.affiliation: Istituto di Endocrinologia ed Oncologia Sperimentale del CNR c/o Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Scuola di Medicina e Chirurgia di Napoli, Università degli Studi di Napoli Federico II, Napoli 80138, Italy.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Fusco
authors.affiliation: Division of Molecular Neurobiology, Department of Neurobiology, National Institute for Basic Biology, Okazaki 444-8787, Japan; Department of Basic Biology, School of Life Science, The Graduate University for Advanced Studies (SOKENDAI), Okazaki 444-8787, Japan; madon@nibb.ac.jp.
authors.forename: Masaharu
authors.initials: M
authors.lastname: Noda
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D005947:Glucose / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D051379:Mice; D018482:Muscle, Skeletal / Q000378:metabolism; D010766:Phosphorylation; D017027:Protein Tyrosine Phosphatases / Q000235:genetics*; D011972:Receptor, Insulin / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism
chemical_list: D007328:Insulin; D014443:Tyrosine; D011972:Receptor, Insulin; D017027:Protein Tyrosine Phosphatases; C098066:Ptprj protein, mouse; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3; D005947:Glucose
keywords: Ptprj-deficient mice; diabetes; insulin receptor; insulin signalling; protein tyrosine phosphatase