Disease relevance of Ptpn6

• To determine the effects of anti-tumor necrosis factor (anti-TNF) therapy in the inflammatory and autoimmune disease in motheaten (me/me) mice, which exhibit a Fas apoptosis signaling defect [1].
• Reduction of arthritis and pneumonitis in motheaten mice by soluble tumor necrosis factor receptor [1].
• Increased numbers of osteoclasts contribute to severe osteopenia in Me(v)/Me(v) mice due to mutation of SHP-1 [2].
• Our data indicate that macrophage hypersensitivity to GM-CSF may be a major factor in motheaten pathogenesis and that HCP may dephosphorylate novel substrates critical in GM-CSF mitogenic signaling [3].
• Role of tumor necrosis factor-alpha in the spontaneous development of pulmonary fibrosis in viable motheaten mutant mice [4].

High impact information on Ptpn6

• Signalling by the W/Kit receptor tyrosine kinase is negatively regulated in vivo by the protein tyrosine phosphatase Shp1 [5].
• In vitro binding studies suggest that Y429 in the cytoplasmic domain of the EPO-R is the binding site for SH-PTP1 [6].
• Mice homozygous for the recessive allelic mutation motheaten (me) or viable motheaten (mev) on chromosome 6 develop severe defects in hematopoiesis [7].
• High resolution mapping localized me to an area tightly linked to Hcph on chromosome 6 [7].
• DNA sequence analyses of cDNA and genomic clones revealed that both the me and mev mutations are point mutations that result in aberrant splicing of the Hcph transcript [7].

Chemical compound and disease context of Ptpn6

• Based on finding that sodium stibogluconate (SSG) inhibited SHP-1, the anti-RCC potential and action mechanism of SSG and SSG/IL-2 in combination were investigated in a murine renal cancer model (Renca) [8].
• Role of host phosphotyrosine phosphatase SHP-1 in the development of murine leishmaniasis [9].
• The tyrosine phosphatase SHP-1 is a negative regulator of osteoclastogenesis and osteoclast resorbing activity: increased resorption and osteopenia in me(v)/me(v) mutant mice [10].

Biological context of Ptpn6

• However, BCR-elicited increases in the tyrosine phosphorylation of several SHP-1-associated phosphoproteins, including CD19, were substantially enhanced in CD45-/SHP-1-, compared to wild-type and CD45- cells [11].
• The me/me phenotype suggests that SHPTP1 negatively regulates macrophage proliferative pathways [12].
• SHP-1 plays an important role in the signal transduction of many cytokine receptors, including the receptor for erythropoietin, by associating via its SH2 domains to the receptors and dephosphorylating key substrates [13].
• They also suggest that such interactions may provide one of the mechanisms that control SHP-1 substrate specificity [13].
• A frameshift mutation in the SHPTP1 gene causes the motheaten (me/me) mouse [12].

Anatomical context of Ptpn6

• The motheaten mutation rescues B cell signaling and development in CD45-deficient mice [11].
• Surprisingly, however, the presence or absence of SHP1 had no effect on the proliferative response of bone marrow-derived cultured mast cells to KL or IL3 ex vivo [14].
• These mice are essentially SHPTP1 null and display multiple hematopoietic abnormalities, most prominently hyperproliferation and inappropriate activation of granulocytes and macrophages [12].
• Furthermore, transduction of primary hematopoietic progenitor cells from viable motheaten mice with these mutant Gab2 molecules also significantly ameliorated their enhanced migration capacity associated with the SHP1 gene mutation [15].
• SHP-1 is an SH2-containing cytoplasmic tyrosine phosphatase that is widely distributed in cells of the hematopoietic system [13].

Associations of Ptpn6 with chemical compounds

• Western blot analysis showed that several proteins that were markedly hyperphosphorylated on tyrosine residues were detected in the motheaten osteoclasts, including a novel 126-kd phosphotyrosine protein [16].
• The protein tyrosine phosphatase SHP-1 regulates integrin-mediated adhesion of macrophages [17].
• SHP-1 is associated with a tyrosine phosphorylated, plasma membrane-spanning glycoprotein, pp130, in colony stimulating factor-1 stimulated or unstimulated macrophages [18].
• Taken together, these data provide the first direct evidence that SHP-1 inhibits macrophage activation by LPS and suggest that this effect may be mediated in part by dephosphorylation of vav1 [19].
• T cell developmental defects in 'viable motheaten' mice deficient in SHP-1 protein-tyrosine phosphatase. Developmental defects are corrected in vitro in the presence of normal hematopoietic-origin stromal cells and in vivo by exogenous IL-7 [20].

Physical interactions of Ptpn6

• Tyrosyl-phosphorylated SHPTP1 binds to Grb2 via the Grb2 SH2 domain [12].
• Other work has shown that c-Abl interacts with the SHPTP1 protein tyrosine phosphatase in induction of SAPK activity by genotoxic stress [21].

Enzymatic interactions of Ptpn6

• P130 and SHPTP1 are further tyrosyl phosphorylated upon CSF-1 stimulation [12].
• The Ets2 transcription factor is constitutively phosphorylated on residue Thr(72) in macrophages derived from mice homozygous for the motheaten viable (me-v) allele of the hemopoietic cell phosphatase (Hcph) gene [22].
• The biochemical basis of this complex trait involves a pathway requiring Lyn to phosphorylate CD22 and recruit SHP-1 to the CD22/BCR complex [23].

Regulatory relationships of Ptpn6

• Using primary bone marrow-derived macrophages from me/me mice and normal littermates, we examined the role of SHPTP1 in regulating signaling by the major macrophage mitogen colony-stimulating factor 1 (CSF-1) (also known as macrophage colony-stimulating factor) [12].
• Fas-induced DNA degradation detected by the terminal deoxynucleotide transferase reaction was also observed in the killing of motheaten thymocytes by a Fas-based CTL as well as by anti-Fas mAb [24].
• Finally, introduction of purified Leishmania EF-1alpha, but not the corresponding host protein into macrophages activated SHP-1 and blocked the induction of inducible nitric-oxide synthase expression in response to interferon-gamma [25].
• We prepared Et-3,4-dephostatin as a stable analogue and found it to inhibit PTP-1B and SHPTP-1 protein-tyrosine phosphatases selectively but not to inhibit CD45 and leukocyte common antigen-related phosphatase ones effectively [26].
• The activity of src-homology 2 domain-containing PTP (SHP-1) was significantly upregulated 1 min after AT2 stimulation [27].

Other interactions of Ptpn6

• These proteins are hyperphosphorylated on tyrosyl residues in me/me macrophages, suggesting that Grb2 may recruit substrates for SHPTP1 [12].
• Regulation of colony-stimulating factor 1 receptor signaling by the SH2 domain-containing tyrosine phosphatase SHPTP1 [12].
• Activated Ets2 is required for persistent inflammatory responses in the motheaten viable model [22].
• Role of the protein tyrosine phosphatase SHP-1 (Src homology phosphatase-1) in the regulation of interleukin-3-induced survival, proliferation and signalling [28].
• Interestingly, several markedly hyperphosphorylated proteins were detected in the motheaten macrophages, including a novel 126-kDa phosphotyrosine protein that associated with the phosphatase via its SH2 domains, suggesting that these proteins depend on HCP for dephosphorylation and may mediate the heightened growth responses to GM-CSF [3].

Analytical, diagnostic and therapeutic context of Ptpn6

• Therefore, we suggest that SHP1 is not actively recruited to inhibit TCR signaling induced by ligation of this receptor alone [29].
• Activation-specific phosphorylation of STAT (signal transducer and activator of transcription) 5a/b, protein kinase B and ERK (extracellular-signal-regulated kinase)-1 and -2 was also unaffected by expression of WT or R459M SHP-1 [28].
• Here, we describe the use of fetal thymic organ culture (FTOC) and bone marrow adoptive transfer to study the effects of SHP-1 deficiency on thymocyte development [20].
• Splenic B cells from viable motheaten mice were isolated and assessed for purity by flow cytometry [30].
• Significantly increased serum TNF-alpha levels were observed by enzyme-linked immunosorbent assay in viable motheaten mice at 4, 6, and 10 weeks of age as compared with normal control littermate mice [4].

References