Protein Tyrosine Phosphatases and Type 1 Diabetes: Genetic and Functional Implications of PTPN2 and PTPN22

Abstract

Protein tyrosine phosphatases (PTPs) play a central role in modulating the transduction of cellular signals, including the cells of the immune system. Several PTPs, PTPN22, PTPN2, and UBASH3A, have been associated with risk of type 1 diabetes (T1D) by genome wide association studies. Based on the current understanding of PTPs, it is clear that these variants impact antigen receptor signaling and cytokine signaling. This impact likely contributes to the development and progression of autoimmunity through multiple mechanisms, including failures of central and peripheral tolerance and the promotion of proinflammatory T cell responses. In this review, we discuss the genetic and functional implications of two of these PTPs, PTPN22 and PTPN2, in the development of T1D. We describe the known roles of these proteins in immune function, and how the expression and function of these proteins is altered by the genetic variants associated with T1D. Yet, there are still controversies in the field that require further study and the development of new approaches to extend our understanding of these PTP variants, with the goal of using the information gained to improve our ability to predict and cure T1D.

Protein‐altering variants of PTPN2 in childhood‐onset Type 1A diabetes

“…Previous GWAS have documented a significant association between PTPN2 ‐flanking SNPs and the risk of Type 1A diabetes . In particular, the G‐G haplotype of rs1893217 and rs2542151 was linked to both low expression levels of PTPN2 and susceptibility to Type 1A diabetes ; however, p.Q286Yfs*24 and p.R350Q in our cases did not reside on the G‐G risk haplotype. Moreover, p.Q286Yfs*24 and p.C232W were located outside of the linkage disequilibrium regions that harbour previously reported risk SNPs.…”

“…Additionally, we identified an exceptionally rare variant, p.R350Q, which was scored as damaging by three in silico programs. It is known that PTPN2 regulates T‐cell receptor‐mediated signalling in CD4+ and CD8+ T cells , and genetic deletion of murine Ptpn2 causes cytokine‐induced apoptosis of β cells . To date, however, PTPN2 coding mutations have not been linked to human disorders.…”

25‐Hydroxyvitamin D3‐enhanced PTPN2 positively regulates periodontal inflammation through the JAK/STAT pathway in human oral keratinocytes and a mouse model of type 2 diabetes mellitus

“…PTPN2, an intracellular tyrosine‐specific phosphatase, was recently found to regulate immune and inflammatory responses in diabetic patients as a protein downstream of the vitamin D receptor (VDR) . In the presence of proinflammatory stimuli, such as TNF‐α and IFN‐γ, or hyperosmotic stress, the nuclear isoform (TC45) of PTPN2 might translocate to the cytoplasm to exert its biological functions . PTPN2 targets several phosphorylated proteins, including epidermal growth factor receptor, insulin receptor, signal transducers and activators of transcription 1 and 3 (STAT1 and STAT3), and Janus kinase (JAK) .…”

Association BetweenPTPN22Polymorphisms and IgE Responses to Staphylococcal Superantigens in Chronic Urticaria

“…As PTPN22 regulate negative activation of T cells, diminished activity of PTPN22 results in hyperresponsiveness of T-cell promoting proinflammatory T-cell responses. 22 , 23 Released cytokines from activated T cells can stimulate B cells to produce specific antibodies. 24 In polymorphic PTPN22 whose activity is diminished, T cells might release higher levels of cytokines which can activate B cells more intensely and result in the increased production of specific IgE against staphylococcal superantigens from B cells.…”