The protein tyrosine phosphatase PTP1B is a negative regulator of CD40 and BAFF-R signaling and controls B cell autoimmunity
03.03.2014
Medgyesi D, Hobeika E, Biesen R, Kollert F, Taddeo A, Voll RE, Hiepe F, Reth M.
J Exp Med. 2014;211(3):427-40
Tyrosine phosphorylation of signaling molecules that mediate B-cell activation in response to various stimuli is tightly regulated by protein tyrosine phosphatases. PTP1B is a ubiquitously expressed tyrosine phosphatase with well-characterized functions in metabolic signaling pathways. We show here that PTP1B negatively regulates CD40, TLR4 and BAFF-R signaling in B cells. Specifically PTP1B counteracts p38 MAPK activation by directly dephosphorylating Tyr182 of this kinase. Mice with a B cell-specific PTP1B-deficiency show increased Tdependent immune responses and elevated total serum IgG. Furthermore, they develop systemic autoimmunity as they have elevated serum anti-dsDNA, spontaneous germinal centers in the spleen and IgG immune complex deposition in the kidney. In a clinical setting, we observed that B cells of rheumatoid arthritis patients have significantly reduced PTP1B expression. Our data suggest that PTP1B plays an important role in the control of B-cell activation and the maintenance of immunological tolerance.
