T Cell Protein Tyrosine Phosphatase in Osteoimmunology

Abstract

Osteoimmunology highlights the two-way communication between bone and immune cells. T cell protein tyrosine phosphatase (TCPTP), also known as protein-tyrosine phosphatase non-receptor 2 (PTPN2), is an intracellular protein tyrosine phosphatase (PTP) essential in regulating immune responses and bone metabolism via dephosphorylating target proteins. Tcptp knockout in systemic or specific immune cells can seriously damage the immune function, resulting in bone metabolism disorders. This review provided fresh insights into the potential role of TCPTP in osteoimmunology. Overall, the regulation of osteoimmunology by TCPTP is extremely complicated. TCPTP negatively regulates macrophages activation and inflammatory factors secretion to inhibit bone resorption. TCPTP regulates T lymphocytes differentiation and T lymphocytes-related cytokines signaling to maintain bone homeostasis. TCPTP is also expected to regulate bone metabolism by targeting B lymphocytes under certain time and conditions. This review offers a comprehensive update on the roles of TCPTP in osteoimmunology, which can be a promising target for the prevention and treatment of inflammatory bone loss.

PTPN2 inhibits the proliferation of psoriatic keratinocytes by dephosphorylation of STAT3

“…When signals from immune and inflammatory responses stimulate cells, TC45 exits the nucleus and dephosphorylates receptor/nonreceptor‐type PTP kinases, such as Janus kinase (JAK), signal transducer and activator of transcription (STAT), 9 and epidermal growth factor receptor, to exert biological effects. Earlier reports have reported that PTPN2 limits the degree of tyrosine phosphorylation of JAKs by regulating the permeability of intestinal epithelial cells and dephosphorylates tyrosines on STAT1 and STAT3, thereby inhibiting cytokine expression mediated by cytokines such as INF‐γ and interleukin‐6 (IL‐6), modulating the signal transduction pathway of extracellular regulatory kinases, and inhibiting cell proliferation and differentiation 10,11 . PTPN2 expression is low in keratinocytes and is upregulated by 25‐hydroxyvitamin D3.…”

“…Earlier reports have reported that PTPN2 limits the degree of tyrosine phosphorylation of JAKs by regulating the permeability of intestinal epithelial cells and dephosphorylates tyrosines on STAT1 and STAT3, thereby inhibiting cytokine expression mediated by cytokines such as INF-γ and interleukin-6 (IL-6), modulating the signal transduction pathway of extracellular regulatory kinases, and inhibiting cell proliferation and differentiation. 10,11 PTPN2 expression is low in keratinocytes and is upregulated by 25-hydroxyvitamin D3. Besides, PTPN2 also dephosphorylates protein substrates in the 8 JAK1/JAK3 signaling pathway and inhibits periodontal inflammation in type 2 diabetes.…”

Upregulation of TCPTP in Macrophages Is Involved in IL‐35 Mediated Attenuation of Experimental Colitis

“…The inflammatory response initialed by hyperactivation of macrophages, such as the release of large amounts of cytokines and chemokines, is the dominant cause in the pathogenesis and continuous progression of UC [ 29 ]. T cell protein tyrosine phosphatase (TCPTP), also known as protein tyrosine phosphatase nonreceptor 2 (PTPN2), is an intracellular protein tyrosine phosphatase (PTP) that is widely expressed in various cells (such as, intestinal epithelial cells, macrophages, and T lymphocytes) and regulates immune responses by dephosphorylating target proteins [ 30 , 31 , 32 , 33 ]. Mutations of gene encoding TCPTP result in various autoimmune diseases such as IBD [ 34 ] and rheumatoid arthritis [ 35 ].…”

“…Mutations of gene encoding TCPTP result in various autoimmune diseases such as IBD [ 34 ] and rheumatoid arthritis [ 35 ]. In vitro and in vivo experiments have proved that TCPTP can regulate multiple signaling pathways [ 36 , 37 , 38 , 39 ] by inhibiting Janus-activated kinases (JAK)/signal transducer and activator of transcription (STAT) [ 30 , 35 , 40 , 41 , 42 , 43 ]. The direct substrates include JAK3, STAT1, and STAT5 [ 44 , 45 , 46 ].…”

Discovery of a selective TC-PTP degrader for cancer immunotherapy

“…2 T-cell protein tyrosine phosphatase (TC-PTP), encoded by PTPN2, is a non-receptor type PTP ubiquitously expressed in all tissues, with highest expression in hematopoietic cells. 3 TC-PTP negatively regulates signaling of non-receptor tyrosine kinases including JAK1 and JAK3, 4,5 receptor tyrosine kinases, 6,7 transcription factors, such as STAT1, 8 STAT3, 9 and STAT5, 5 and Src family kinases, including LCK. 10 Recently, accumulated evidence has suggested that TC-PTP is an attractive target for cancer immunotherapy.…”