Disease relevance of PTPN6

• PTPN6 maps to 12p13, a region commonly involved in leukemia-associated chromosomal abnormalities [1].
• Expression of SHP-1 phosphatase, a key negative regulator of cell signaling, is lost in T cell lymphomas and other malignancies due to DNA methylation of the SHP-1 promoter by a currently undefined mechanism [2].
• SOCS1 and SHP1 hypermethylation in multiple myeloma: implications for epigenetic activation of the Jak/STAT pathway [3].
• Recruitment of the SH2 domain containing cytoplasmic protein-tyrosine phosphatase SHP-1 to the membrane by somatostatin (SST) is an early event in its antiproliferative signaling that induces intracellular acidification-dependent apoptosis in breast cancer cells [4].
• We have previously shown that the protein tyrosine phosphatase SHP-1 (Src-homology 2 domain containing phosphatase-1) is activated during Leishmania infection and plays an important role in both the survival of Leishmania within cultured macrophages and disease progression in vivo by inhibiting nitric oxide production [5].

Psychiatry related information on PTPN6

• For both the control group and the left HCP group, a linear increase in reaction time as a function of angle of rotation was found [6].

High impact information on PTPN6

• The natural killer inhibitory receptors fulfill this function by recruiting the tyrosine phosphatase SHP-1 through a cytoplasmic immunoreceptor tyrosine-based inhibition motif [7].
• Upon ligand binding and activation, the inhibitory NK cell receptors become tyrosine phosphorylated and recruit tyrosine phosphatases, SHP-1 and possibly SHP-2, resulting in inhibition of NK cell-mediated cytotoxicity and cytokine expression [8].
• The activated Jaks phosphorylate both themselves and the receptor subunits, creating docking sites for SH2-containing proteins including SHC, which couples receptor engagement to activation of the ras pathway, and HCP, a protein tyrosine phosphatase which negatively affects the response [9].
• To address the necessity, interaction, or redundancy of these signaling molecules, we have generated SHP-1- or SHIP-deficient B cell lines and determined their ability to mediate inhibitory signaling [10].
• SHP-1-mediated inhibitory signaling blocks apoptosis, while SHIP recruitment attenuates a proapoptotic signal initiated by Fc gammaRIIB [10].

Chemical compound and disease context of PTPN6

• Inhibitory and stimulatory effects of somatostatin on two human pancreatic cancer cell lines: a primary role for tyrosine phosphatase SHP-1 [11].
• Octapeptide somatostatin analog SMS 201-995 induces translocation of intracellular PTP1C to membranes in MCF-7 human breast adenocarcinoma cells [12].
• Finally, phosphorylation of SH-PTP1 could be provoked in permeabilized platelets by thrombin or GTP gamma S. This was abolished by pertussis toxin, the specificity of this effect being verified with the megakaryocytic cell line Dami cell [13].
• In addition, treatment of U-937 human myeloid leukemia cells with 1-beta-D-arabinofuranosylcytosine (ara-C) was associated with induction of the PKCdelta kinase function and inhibition of SHPTP1 activity [14].
• Lack of phosphotyrosine phosphatase SHP-1 expression in malignant T-cell lymphoma cells results from methylation of the SHP-1 promoter [15].

Biological context of PTPN6

• STAT3- and DNA methyltransferase 1-mediated epigenetic silencing of SHP-1 tyrosine phosphatase tumor suppressor gene in malignant T lymphocytes [2].
• The overall survivals of patients with and without SHP1 methylation were similar [3].
• Concomitant with increasing SHP1, a parallel down-regulation of phosphorylated STAT3 occurred, so that by day 5 phosphorylated STAT3 was barely detectable [3].
• Moreover, we determined that these residues, upon phosphorylation, associate with the protein-tyrosine phosphatase SHP-1 [16].
• GH is also shown to activate by 3-4-fold SHP-1, a phosphotyrosine phosphatase that contains two src homology 2 (SH2) domains [17].

Anatomical context of PTPN6

• Three nonhematopoietic PTPN6 transcripts were identified in a variety of cell lines and were shown to be transcribed from a common promoter [18].
• We have used panels of somatic cell hybrids and fluorescent in situ hybridization to determine the chromosomal localization of the novel nontransmembrane tyrosine phosphatase PTPN6 (protein tyrosine phosphatase, nonreceptor type 6), which contains two SH2 domains [1].
• SHP-1 requires inhibitory co-receptors to down-modulate B cell antigen receptor-mediated phosphorylation of cellular substrates [19].
• The protein-tyrosine phosphatase SHP-1 associates with the phosphorylated immunoreceptor tyrosine-based activation motif of Fc gamma RIIa to modulate signaling events in myeloid cells [20].
• High expression of inhibitory receptor SHPS-1 and its association with protein-tyrosine phosphatase SHP-1 in macrophages [21].

Associations of PTPN6 with chemical compounds

• Chromosomal localization of an SH2-containing tyrosine phosphatase (PTPN6) [1].
• Treatment with 5-azacytidine led to progressive demethylation of SHP1 on days 2 to 5, with consequent increasing reexpression of SHP1 as shown by reverse transcription-polymerase chain reaction (RT-PCR) [3].
• Phosphotyrosine 1173 mediates binding of the protein-tyrosine phosphatase SHP-1 to the epidermal growth factor receptor and attenuation of receptor signaling [22].
• A prominent tyrosine-phosphorylated protein of approximately 100 kDa (designated pp100) in epidermal growth factor (EGF)-stimulated A431 cells was found to be a main interaction partner of the protein-tyrosine phosphatase SHP-1 in pull-down experiments with a glutathione S-transferase-SHP-1 fusion protein [23].
• Moreover, treatment of PC12 cells with bradykinin is associated with inhibition in tyrosine phosphorylation of RAFTK in the presence of SHPTP1 [24].

Physical interactions of PTPN6

• We mapped the EGFR phosphotyrosine 1173 as the major binding site for SHP-1 by a combination of phosphopeptide activation, phosphopeptide competition, and receptor YF mutant analysis [22].
• The present studies demonstrate that RAFTK binds constitutively to the protein tyrosine phosphatase SHPTP1 [24].
• Based on the presence of a putative SHP-1 SH2-binding site within the TFG sequences, we have investigated the role of the SHP-1 phosphatase in TRK-T3 oncoprotein signaling [25].
• In monocytes, phosphorylation of LIR-1 and LIR-2 results in the binding of the tyrosine phosphatase SHP-1 [26].
• Therefore, receptor dephosphorylation may be the result of the combined activity of receptor-bound SHP-1 and SHP-1 bound to an auxiliary docking protein [22].

Enzymatic interactions of PTPN6

• The protein-tyrosine phosphatase SHP-1 binds to and dephosphorylates the epidermal growth factor receptor (EGFR), and both SH2 domains of SHP-1 are important for this interaction (Tenev, T., Keilhack, H., Tomic, S., Stoyanov, B., Stein-Gerlach, M., Lammers, R., Krivtsov, A. V., Ullrich, A., and Böhmer, F. D. (1997) J. Biol. Chem. 272, 5966-5973) [22].
• The protein-tyrosine phosphatase SHP-1 binds to and dephosphorylates p120 catenin [23].
• After BCR stimulation in apoptotic cells, SHP-1 has been shown to be recruited to phosphorylated immunoreceptor tyrosine-based inhibitory motifs present in receptors such as CD22 and CD72 [27].
• COS cell-expressed glutathione S-transferase-SHP-1L can dephosphorylate tyrosine-phosphorylated ZAP70 [28].
• In order to study whether there was any correlation between SHP-1 protein expression and tyrosine phosphorylated state of JAK3, the state of phosphorylation of JAK3 was studied in the T cell line HUT-78, and found to be highly phosphorylated [29].

Regulatory relationships of PTPN6

• Substrate phosphorylation was restored by expression of dominant negative mutants of SHP-1, whereas the SHP-1 mutants failed to enhance phosphorylation of the cellular substrates in the absence of CD72 [19].
• Positive effects of SH2 domain-containing tyrosine phosphatase SHP-1 on epidermal growth factor- and interferon-gamma-stimulated activation of STAT transcription factors in HeLa cells [30].
• Here we report that Fc gamma RIIa clustering induces SHP-1 phosphatase activity in THP-1 cells [20].
• Various mutants of SHP-1 were transiently expressed in 293 or COS-7 cells and analyzed for their capacity to associate with immobilized autophosphorylated EGF receptor in vitro and to dephosphorylate coexpressed EGF receptor in intact cells [31].
• In this study, we examined the possible role of SHP-1 in regulating FLT3 signaling [32].

Other interactions of PTPN6

• Finally, we have also observed SDF-1alpha-induced activation and association of the tyrosine phosphatase Shp1 with the CXCR4 in a Galpha(i)-dependent manner [33].
• Beta-chemokine receptor CCR5 signals through SHP1, SHP2, and Syk [34].
• Upon BCR ligation, SHP-1 has been shown to associate with the BCR, the cytoplasmic protein-tyrosine kinases Lyn and Syk, and the inhibitory co-receptors CD22 and CD72 [19].
• Furthermore, we observed that SHP1 associated with RAFTK [34].
• Interaction of growth hormone-activated STATs with SH2-containing phosphotyrosine phosphatase SHP-1 and nuclear JAK2 tyrosine kinase [17].

Analytical, diagnostic and therapeutic context of PTPN6

• Characterization of the 5' ends of the PTPN6 mRNAs by RT-PCR and analysis of the flanking genomic sequences identified putative initiation sites within the two promoters [18].
• How SHP-1 is activated by BCR ligation and regulates BCR signaling is, however, not fully understood [19].
• Total cellular PTPase activity was slightly increased, but SHP-1 activity could not be detected; its absence in this cell line was confirmed by Western blot [11].
• Furthermore, we have found that SHP-1 expression is greatly decreased or undetectable in a number of IL-2 independent HTLV-I transformed T cell lines that exhibit constitutive Jak/signal transducer/activator of transcription activation [35].
• Immunoprecipitation experiments revealed that beta-catenin is one of the main binding partners and a substrate for SHP-1 [36].

References