PTPN2

Case study 1: Taylor M Triolo, 2022

Type 1 diabetes is a polygenic disease that results in an autoimmune response directed against insulin-producing beta cells. PTPN2 is a known high-risk type 1 diabetes associated gene expressed in both immune- and pancreatic beta cells, but how genes affect the development of autoimmune diabetes is largely unknown. The researchers employed CRISPR/Cas9 technology to generate a functional knockout of PTPN2 in human pluripotent stem cells (hPSC) followed by differentiating stem-cell-derived beta-like cells (sBC) and detailed phenotypical analyses. The differentiation efficiency of PTPN2 knockout (PTPN2 KO) sBC is comparable to wild-type (WT) control sBC. Global transcriptomics and protein assays revealed the increased expression of HLA Class I molecules in PTPN2 KO sBC at a steady state and upon exposure to proinflammatory culture conditions, indicating a potential for the increased immune recognition of human beta cells upon differential PTPN2 expression. sBC co-culture with autoreactive preproinsulin-reactive T cell transductants confirmed increased immune stimulations by PTPN2 KO sBC compared to WT sBC.

Fig1. Representative Western blot analysis for the PTPN2 protein or endogenous control protein Cyclophilin B of sorted day 23 GFP+ sBCs from WT and PTPN2 KO.

Fig2. PTPN2 KO sBC displayed increased HLA class I expression.

Case study 2: Lu Chen, 2021

Reversible phosphorylation has emerged as an important mechanism for regulating 26S proteasome function in health and disease. Over 100 phospho-tyrosine sites of the human proteasome have been detected, and yet their function and regulation remain poorly understood. Here the researchers show that the 19S subunit Rpt2 is phosphorylated at Tyr439, a strictly conserved residue within the C-terminal HbYX motif of Rpt2 that is essential for 26S proteasome assembly. Unexpectedly, they found that Y439 phosphorylation depends on Rpt2 membrane localization mediated by its N-myristoylation. Multiple receptors tyrosine kinases can trigger Rpt2-Y439 phosphorylation by activating Src, a N-myristoylated tyrosine kinase. Src directly phosphorylates Rpt2-Y439 in vitro and negatively regulates 26S proteasome activity at cellular membranes, which can be reversed by the membrane-associated isoform of protein tyrosine phosphatase nonreceptor type 2 (PTPN2). In H1975 lung cancer cells with activated Src, blocking Rpt2-Y439 phosphorylation by the Y439F mutation conferred partial resistance to the Src inhibitor saracatinib both in vitro and in a mouse xenograft tumor model, and caused significant changes of cellular responses to saracatinib at the proteome level.

Fig3. Flag-PTPN2 isoforms were expressed in 293T cells. Co-immunoprecipitation of PTPN2 and endogenous proteasome subunits was determined by western blot. CS, C216S.

Fig4. Rpt2-IF-WT/Y439F was immunoprecipitated from pervanadate-treated 293T cells and incubated with bacterially purified His-PTPN2-WT/C216S in an in vitro phosphatase assay.

Fig1. Protein tyrosine phosphatases regulate cytokine receptor–JAK–STAT signaling. (Kelly A Pike, 2016)

Fig2. PTP1B and TCPTP in insulin and leptin signaling. (Tony Tiganis, 2013)

PTPN2 involved in several pathways and played different roles in them. We selected most pathways PTPN2 participated on our site, such as Jak-STAT signaling pathway, which may be useful for your reference. Also, other proteins which involved in the same pathway with PTPN2 were listed below. Creative BioMart supplied nearly all the proteins listed, you can search them on our site.

PTPN2 has several biochemical functions, for example, integrin binding, protein binding, protein kinase binding. Some of the functions are cooperated with other proteins, some of the functions could acted by PTPN2 itself. We selected most functions PTPN2 had, and list some proteins which have the same functions with PTPN2. You can find most of the proteins on our site.

PTPN2 has direct interactions with proteins and molecules. Those interactions were detected by several methods such as yeast two hybrid, co-IP, pull-down and so on. We selected proteins and molecules interacted with PTPN2 here. Most of them are supplied by our site. Hope this information will be useful for your research of PTPN2.

GHR; ITGA1; WASL; CDC42; INSR; SFN; UCHL5; q5ni33_fratt; PSMC1; EGFR