Veillette André, Rhee Inmoo, Souza Cleiton Martins, Davidson Dominique
Laboratory of Molecular Oncology, Clinical Research Institute of Montréal, Montréal, Québec, Canada.
Immunol Rev. 2009 Mar;228(1):312-24. doi: 10.1111/j.1600-065X.2008.00747.x.
The proline-, glutamic acid-, serine- and threonine-rich (PEST) family of protein tyrosine phosphatases (PTPs) includes proline-enriched phosphatase (PEP)/lymphoid tyrosine phosphatase (LYP), PTP-PEST, and PTP-hematopoietic stem cell fraction (HSCF). PEP/LYP is a potent inhibitor of T-cell activation, principally by suppressing the activity of Src family protein tyrosine kinases (PTKs). This function seems to be dependent, at least in part, on the ability of PEP to bind C-terminal Src kinase (Csk), a PTK also involved in inactivating Src kinases. Interestingly, a polymorphism of LYP in humans (R620W) is a significant risk factor for autoimmune diseases including type 1 diabetes, rheumatoid arthritis, and lupus. The R620W mutation may be a 'gain-of-function' mutation. In non-hematopoietic cells, PTP-PEST is a critical regulator of adhesion and migration. This effect correlates with the aptitude of PTP-PEST to dephosphorylate cytoskeletal proteins such as Cas, focal adhesion associated-kinase (FAK), Pyk2, and PSTPIP. While not established, a similar function may also exist in immune cells. Additionally, overexpression studies provided an indication that PTP-PEST may be a negative regulator of lymphocyte activation. Interestingly, mutations in a PTP-PEST- and PTP-HSCF-interacting protein, PSTPIP1, were identified in humans with pyogenic sterile arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome and familial recurrent arthritis, two autoinflammatory diseases. These mutations abrogate the ability of PSTPIP1 to bind PTP-PEST and PTP-HSCF, suggesting that these two PTPs may be negative regulators of inflammation.
富含脯氨酸、谷氨酸、丝氨酸和苏氨酸的（PEST）蛋白酪氨酸磷酸酶（PTP）家族包括富含脯氨酸的磷酸酶（PEP）/淋巴细胞酪氨酸磷酸酶（LYP）、PTP-PEST和PTP-造血干细胞组分（HSCF）。PEP/LYP是T细胞活化的强效抑制剂，主要通过抑制Src家族蛋白酪氨酸激酶（PTK）的活性来实现。该功能似乎至少部分取决于PEP结合C末端Src激酶（Csk）的能力，Csk也是一种参与使Src激酶失活的PTK。有趣的是，人类LYP的一种多态性（R620W）是包括1型糖尿病、类风湿性关节炎和狼疮在内的自身免疫性疾病的重要危险因素。R620W突变可能是一种“功能获得性”突变。在非造血细胞中，PTP-PEST是黏附与迁移的关键调节因子。这种作用与PTP-PEST使细胞骨架蛋白（如Cas、粘着斑相关激酶（FAK）、Pyk2和PSTPIP）去磷酸化的能力相关。虽然尚未确定，但免疫细胞中可能也存在类似功能。此外，过表达研究表明PTP-PEST可能是淋巴细胞活化的负调节因子。有趣的是，在患有化脓性无菌性关节炎、坏疽性脓皮病和痤疮（PAPA）综合征以及家族性复发性关节炎（两种自身炎症性疾病）的人类中，发现了一种与PTP-PEST和PTP-HSCF相互作用的蛋白PSTPIP1发生了突变。这些突变消除了PSTPIP1结合PTP-PEST和PTP-HSCF的能力，表明这两种PTP可能是炎症的负调节因子。
