title: LYP inhibits T-cell activation when dissociated from CSK.
abstract: Lymphoid tyrosine phosphatase (LYP) and C-terminal Src kinase (CSK) are negative regulators of signaling mediated through the T-cell antigen receptor (TCR) and are thought to act in a cooperative manner when forming a complex. Here we studied the spatiotemporal dynamics of the LYP-CSK complex in T cells. We demonstrate that dissociation of this complex is necessary for recruitment of LYP to the plasma membrane, where it downmodulates TCR signaling. Development of a potent and selective chemical probe of LYP confirmed that LYP inhibits T-cell activation when removed from CSK. Our findings may explain the reduced TCR-mediated signaling associated with a single-nucleotide polymorphism that confers increased risk for certain autoimmune diseases, including type 1 diabetes and rheumatoid arthritis, and results in expression of a mutant LYP that is unable to bind CSK. Our compound also represents a starting point for the development of a LYP-based treatment of autoimmunity.
authors.affiliation: Infectious and Inflammatory Disease Center, Sanford-Burnham Medical Research Institute, La Jolla, California, USA.
authors.forename: Torkel
authors.initials: T
authors.lastname: Vang
authors.forename: Wallace H
authors.initials: WH
authors.lastname: Liu
authors.forename: Laurence
authors.initials: L
authors.lastname: Delacroix
authors.forename: Shuangding
authors.initials: S
authors.lastname: Wu
authors.forename: Stefan
authors.initials: S
authors.lastname: Vasile
authors.forename: Russell
authors.initials: R
authors.lastname: Dahl
authors.forename: Li
authors.initials: L
authors.lastname: Yang
authors.forename: Lucia
authors.initials: L
authors.lastname: Musumeci
authors.forename: Dana
authors.initials: D
authors.lastname: Francis
authors.forename: Johannes
authors.initials: J
authors.lastname: Landskron
authors.forename: Kjetil
authors.initials: K
authors.lastname: Tasken
authors.forename: Michel L
authors.initials: ML
authors.lastname: Tremblay
authors.forename: Benedicte A
authors.initials: BA
authors.lastname: Lie
authors.forename: Rebecca
authors.initials: R
authors.lastname: Page
authors.forename: Tomas
authors.initials: T
authors.lastname: Mustelin
authors.forename: Souad
authors.initials: S
authors.lastname: Rahmouni
authors.forename: Robert C
authors.initials: RC
authors.lastname: Rickert
authors.forename: Lutz
authors.initials: L
authors.lastname: Tautz
mesh_terms: D000081247:CSK Tyrosine-Protein Kinase; D002462:Cell Membrane / Q000378:metabolism; D015536:Down-Regulation; D006801:Humans; D008213:Lymphocyte Activation; D011485:Protein Binding; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism*; D019061:src-Family Kinases
chemical_list: D011948:Receptors, Antigen, T-Cell; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human; C516765:PTPN22 protein, human; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22