TY - JOUR
T1 - Autoimmune-associated PTPN22 R620W variation reduces phosphorylation of lymphoid phosphatase on an inhibitory tyrosine residue
AU - Fiorillo, Edoardo
AU - Orrú, Valeria
AU - Stanford, Stephanie M.
AU - Liu, Yingge
AU - Salek, Mogjiborahman
AU - Rapini, Novella
AU - Schenone, Aaron D.
AU - Saccucci, Patrizia
AU - Delogu, Lucia G.
AU - Angelini, Federica
AU - Bitti, Maria Luisa Manca
AU - Schmedt, Christian
AU - Chan, Andrew C.
AU - Acuto, Oreste
AU - Bottini, Nunzio
PY - 2010/8/20
Y1 - 2010/8/20
N2 - 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.
AB - 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.
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U2 - 10.1074/jbc.M110.111104
DO - 10.1074/jbc.M110.111104
M3 - Article
C2 - 20538612
AN - SCOPUS:77956216562
SN - 0021-9258
VL - 285
SP - 26506
EP - 26518
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 34
ER -