Disease relevance of PTPN2

• Furthermore, retrovirus-mediated overexpression of the nuclear isoform of TC-PTP suppressed the IL-6-induced growth arrest of myeloid leukemia M1 cells [1].
• Here, we review the function of PTP1B and TC-PTP in diabetes, obesity, and processes related to cancer [2].
• We demonstrate here that scAAV-TC-PTP vectors serve as a helper virus in augmenting the transduction efficiency of conventional AAV vectors in vitro as well as in vivo which correlates directly with the extent of second-strand DNA synthesis of conventional single-stranded AAV vectors [3].
• Adeno-associated virus type 2-mediated gene transfer: role of cellular T-cell protein tyrosine phosphatase in transgene expression in established cell lines in vitro and transgenic mice in vivo [4].
• Purification and characterization of a human recombinant T-cell protein-tyrosine-phosphatase from a baculovirus expression system [5].
• Gene Dosage - The heterozygous knock-out mice have increased susceptibility to inflammatory bowel disease (ulcerative colitis and Crohn’s disease) [6].

High impact information on PTPN2

• Cytoplasmic protein tyrosine phosphatases, regulation and function: the roles of PTP1B and TC-PTP [7].
• The cytoplasmic tail of alpha(1) integrin selectively interacts with a ubiquitously expressed protein tyrosine phosphatase TCPTP (T-cell protein tyrosine phosphatase) and activates it after cell adhesion to collagen [8].
• We found distinct expression profiles of tyrosine phosphatases in DLBCL subtypes and identified putative STAT6 tyrosine phosphatases-protein tyrosine phosphatase nonreceptor type 1 (PTPN1) and PTPN2, whose expression is significantly higher in ABC-like DLBCL [9].
• Here we show that PTP1B and TCPTP function in a coordinated and temporally distinct manner to achieve an overall regulation of IR phosphorylation and signaling [10].
• We have now purified a Stat1 PTP activity from HeLa cell nuclear extract and identified it as TC45, the nuclear isoform of the T-cell PTP (TC-PTP) [11].

Chemical compound and disease context of PTPN2

• Involvement of the small protein tyrosine phosphatases TC-PTP and PTP1B in signal transduction and diseases: from diabetes, obesity to cell cycle, and cancer [2].

Biological context of PTPN2

• Isolation and mapping of human T-cell protein tyrosine phosphatase sequences: localization of genes and pseudogenes discriminated using fluorescence hybridization with genomic versus cDNA probes [12].
• To address this, four genomic clones were obtained with homology to the TC PTP cDNA and characterized for their primary structure and their position within the human genome [12].
• T-cell protein tyrosine phosphatase (TCPTP) exists as two forms generated by alternative splicing: a 48-kDa endoplasmic reticulum (ER)-associated form (TC48) and a 45-kDa nuclear form (TC45) [13].
• Association of the T-cell protein tyrosine phosphatase with nuclear import factor p97 [14].
• Arginine methylation of STAT1 regulates its dephosphorylation by T cell protein tyrosine phosphatase [15].

Anatomical context of PTPN2

• Reconstitution of TC-PTP-null MEFs with TC45, but not the endoplasmic reticulum (ER)-associated isoform TC48, rescues the defect in Stat1 dephosphorylation [11].
• Furthermore, the dephosphorylation of IFN-induced tyrosine-phosphorylated Stat1 is defective in TC-PTP-null mouse embryonic fibroblasts (MEFs) and primary thymocytes [11].
• The TCPTP D182A substrate-trapping mutants were transiently overexpressed in COS cells, and their ability to form complexes with tyrosine-phosphorylated (pTyr) proteins was assessed [13].
• A novel mechanism for imatinib mesylate (STI571) resistance in CML cell line KT-1: role of TC-PTP in modulating signals downstream from the BCR-ABL fusion protein [16].
• We show that the proliferative response of lymphocytes was greatly increased when cultured as a purified population, indicating that an inhibitory population is present in TC-PTP(-/-) spleen [17].

Associations of PTPN2 with chemical compounds

• To identify TCPTP substrates, we have generated substrate-trapping mutants, in which the invariant catalytic acid of TCPTP (D182) is mutated to alanine [13].
• Therefore, we examined whether the suppression of TC-PTP expression might contribute to imatinib mesylate-resistance in KTR cells [16].
• Unlike wild-type TCPTP, the R49K derivative preferred tyrosine to aspartic or glutamic acid [18].
• Cys 121 is highly conserved among phosphatases, and ABDF also inhibits TC-PTP and LAR [19].
• With readily access to key intermediates, we utilized a solution phase parallel synthesis approach and rapidly identified a highly potent PTP1B inhibitor (19, K(i)=76 nM) with moderate selectivity (5-fold) over T-cell PTPase (TCPTP) through interacting with a second phosphotyrosine binding site (site 2) in the close proximity to the catalytic site [20].

Physical interactions of PTPN2

• Endogenous TC-PTP complexed with STAT3 in the nucleus of M1 cells [1].
• 5. The catalytic domain and full-length versions of TCPTP bound a potent inhibitor with affinities similar to those of PTP-1B [21].

Enzymatic interactions of PTPN2

• The T-cell protein tyrosine phosphatase is phosphorylated on Ser-304 by cyclin-dependent protein kinases in mitosis [22].
• TCPTP dephosphorylates VEGFR2 in a phosphosite-specific manner, inhibits its kinase activity and prevents its internalization from the cell surface [23].

Regulatory relationships of PTPN2

• Here, we demonstrate that IL-6-induced tyrosine-phosphorylation and activation of STAT3 were suppressed by overexpression of the nuclear isoform of TC-PTP in 293T cells [1].

Other interactions of PTPN2

• The nuclear isoform of protein-tyrosine phosphatase TC-PTP regulates interleukin-6-mediated signaling pathway through STAT3 dephosphorylation [1].
• These results strongly suggest that the nuclear isoform of TC-PTP may serve as a negative regulator of IL-6-mediated signaling pathway [1].
• In the previous study, we demonstrated that the nuclear isoform of T-cell protein-tyrosine phosphatase (TC-PTP) dephosphorylated and deactivated signal transducer and activator of transcription 5a (STAT5a) and STAT5b, thereby negatively regulating prolactin (PRL)-mediated signaling pathway [1].
• This work reports the isolation, partial characterization, and chromosomal mapping of several human T-cell protein tyrosine phosphatase (PTPase) sequences and provides a direct comparison of the specificity of cDNA versus genomic probes in discriminating the location of genes versus pseudogenes by fluorescence in situ hybridization [12].
• Purification and characterization of T cell protein tyrosine phosphatase reveals significant functional homology to protein tyrosine phosphatase-1B [21].

Analytical, diagnostic and therapeutic context of PTPN2

• By affinity chromatography, using GST-TCPTP fusion proteins, we have isolated three cytoplasmic proteins of 120, 116, and 97 kDa that interact with TCPTP [14].
• We show that a Gr-1(+)-enriched cell population isolated from TC-PTP(-/-) mice suppresses the CD3-induced proliferation of T cells in coculture in vitro [17].
• Detailed enzyme kinetic analysis with a set of wild-type and mutant PTPs, X-ray protein crystallography, and molecular modeling studies confirmed that selectivity for PTP1B and TC-PTP was achieved due to steric hindrance imposed by bulky position 259 residues in other PTPs [24].
• Sequences specific to and homologous to human T-cell PTPase (TC-PTP) were found in the genomic clones of PTP-S, which are expressed in rat cells, as determined by using a specific probe and Northern blot analysis [25].
• Analysis by confocal microscopy revealed that, in TC-PTP ko MEFs, activated PDGF beta-receptors colocalized with Rab4a, a marker for rapid recycling [26].

References