title: Protein tyrosine phosphatase receptor type γ is a JAK phosphatase and negatively regulates leukocyte integrin activation.
abstract: Regulation of signal transduction networks depends on protein kinase and phosphatase activities. Protein tyrosine kinases of the JAK family have been shown to regulate integrin affinity modulation by chemokines and mediated homing to secondary lymphoid organs of human T lymphocytes. However, the role of protein tyrosine phosphatases in leukocyte recruitment is still elusive. In this study, we address this issue by focusing on protein tyrosine phosphatase receptor type γ (PTPRG), a tyrosine phosphatase highly expressed in human primary monocytes. We developed a novel methodology to study the signaling role of receptor type tyrosine phosphatases and found that activated PTPRG blocks chemoattractant-induced β2 integrin activation. Specifically, triggering of LFA-1 to high-affinity state is prevented by PTPRG activation. High-throughput phosphoproteomics and computational analyses show that PTPRG activation affects the phosphorylation state of at least 31 signaling proteins. Deeper examination shows that JAKs are critically involved in integrin-mediated monocyte adhesion and that PTPRG activation leads to JAK2 dephosphorylation on the critical 1007-1008 phosphotyrosine residues, implying JAK2 inhibition and thus explaining the antiadhesive role of PTPRG. Overall, the data validate a new approach to study receptor tyrosine phosphatases and show that, by targeting JAKs, PTPRG downmodulates the rapid activation of integrin affinity in human monocytes, thus emerging as a potential novel critical regulator of leukocyte trafficking.
authors.affiliation: Division of General Pathology, Department of Pathology and Diagnostics, School of Medicine, University of Verona, Verona 37134, Italy; and.
authors.forename: Michela
authors.initials: M
authors.lastname: Mirenda
authors.affiliation: Division of General Pathology, Department of Pathology and Diagnostics, School of Medicine, University of Verona, Verona 37134, Italy; and Center for Biomedical Computing, University of Verona, Verona 37134, Italy.
authors.forename: Lara
authors.initials: L
authors.lastname: Toffali
authors.affiliation: Division of General Pathology, Department of Pathology and Diagnostics, School of Medicine, University of Verona, Verona 37134, Italy; and Center for Biomedical Computing, University of Verona, Verona 37134, Italy.
authors.forename: Alessio
authors.initials: A
authors.lastname: Montresor
authors.affiliation: Center for Biomedical Computing, University of Verona, Verona 37134, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Scardoni
authors.affiliation: Division of General Pathology, Department of Pathology and Diagnostics, School of Medicine, University of Verona, Verona 37134, Italy; and.
authors.forename: Claudio
authors.initials: C
authors.lastname: Sorio
authors.affiliation: Division of General Pathology, Department of Pathology and Diagnostics, School of Medicine, University of Verona, Verona 37134, Italy; and Center for Biomedical Computing, University of Verona, Verona 37134, Italy carlo.laudanna@univr.it.
authors.forename: Carlo
authors.initials: C
authors.lastname: Laudanna
mesh_terms: D000595:Amino Acid Sequence; D018821:CD18 Antigens / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D002448:Cell Adhesion; D002465:Cell Movement; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008969:Molecular Sequence Data; D009000:Monocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D010766:Phosphorylation; D061251:Primary Cell Culture; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D018821:CD18 Antigens; D016169:Lymphocyte Function-Associated Antigen-1; D010750:Phosphoproteins; C507924:JAK2 protein, human; D053614:Janus Kinase 2; C516850:PTPRG protein, human; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5