A missense C1858T single nucleotide polymorphism in the PTPN22 gene recently emerged as a major risk factor for human autoimmunity. PTPN22 encodes the lymphoid tyrosine phosphatase (LYP), which forms a complex with the kinase Csk and is a critical negative regulator of signaling through the T cell receptor. The C1858T single nucleotide polymorphism results in the LYP-R620W variation within the LYP-Csk interaction motif. LYP-W620 exhibits a greatly reduced interaction with Csk and is a gain-of-function inhibitor of signaling. Here we show that LYP constitutively interacts with its substrate Lck in a Csk-dependent manner. T cell receptor-induced phosphorylation of LYP by Lck on an inhibitory tyrosine residue releases tonic inhibition of signaling by LYP. The R620W variation disrupts the interaction between Lck and LYP, leading to reduced phosphorylation of LYP, which ultimately contributes to gain-of-function inhibition of T cell signaling.

Fiorillo, E., Orrú, V., Stanford, S., Liu, Y., Salek, M., Rapini, N., et al. (2010). Autoimmune-associated PTPN22 R620W variation reduces phosphorylation of lymphoid phosphatase on an inhibitory tyrosine residue. JOURNAL OF BIOLOGICAL CHEMISTRY, 285(34), 26506-26518 [10.1074/jbc.M110.111104].

Autoimmune-associated PTPN22 R620W variation reduces phosphorylation of lymphoid phosphatase on an inhibitory tyrosine residue

SACCUCCI, PATRIZIA;ANGELINI, FEDERICA;MANCA BITTI, MARIA LUISA;BOTTINI, NUNZIO
2010-08-20

Abstract

A missense C1858T single nucleotide polymorphism in the PTPN22 gene recently emerged as a major risk factor for human autoimmunity. PTPN22 encodes the lymphoid tyrosine phosphatase (LYP), which forms a complex with the kinase Csk and is a critical negative regulator of signaling through the T cell receptor. The C1858T single nucleotide polymorphism results in the LYP-R620W variation within the LYP-Csk interaction motif. LYP-W620 exhibits a greatly reduced interaction with Csk and is a gain-of-function inhibitor of signaling. Here we show that LYP constitutively interacts with its substrate Lck in a Csk-dependent manner. T cell receptor-induced phosphorylation of LYP by Lck on an inhibitory tyrosine residue releases tonic inhibition of signaling by LYP. The R620W variation disrupts the interaction between Lck and LYP, leading to reduced phosphorylation of LYP, which ultimately contributes to gain-of-function inhibition of T cell signaling.
20-ago-2010
Pubblicato
Rilevanza internazionale
Articolo
Sì, ma tipo non specificato
Settore MED/01 - STATISTICA MEDICA
Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA
English
Con Impact Factor ISI
Protein-Tyrosine Kinases; Cells, Cultured; Lymphocyte Specific Protein Tyrosine Kinase p56(lck); Receptors, Antigen, T-Cell; Tyrosine; Animals; T-Lymphocytes; Humans; Mutation, Missense; Autoimmunity; Signal Transduction; Mice; Proto-Oncogene Proteins; Protein Tyrosine Phosphatase, Non-Receptor Type 22; Phosphorylation
http://www.jbc.org/content/285/34/26506.long
Fiorillo, E., Orrú, V., Stanford, S., Liu, Y., Salek, M., Rapini, N., et al. (2010). Autoimmune-associated PTPN22 R620W variation reduces phosphorylation of lymphoid phosphatase on an inhibitory tyrosine residue. JOURNAL OF BIOLOGICAL CHEMISTRY, 285(34), 26506-26518 [10.1074/jbc.M110.111104].
Fiorillo, E; Orrú, V; Stanford, S; Liu, Y; Salek, M; Rapini, N; Schenone, A; Saccucci, P; Delogu, L; Angelini, F; MANCA BITTI, Ml; Schmedt, C; Chan, A; Acuto, O; Bottini, N
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/16404
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