Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “SHP”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 469 records · Page 26Linked to original sources
PubMed2001

Mutation of the hematopoietic cell phosphatase (Hcph) gene is associated with resistance to gamma-irradiation-induced apoptosis in Src homology protein tyrosine phosphatase (SHP)-1-deficient "motheaten" mutant mice.

To determine the role of Src homology protein tyrosine phosphatase (SHP-1) in the ionizing radiation-induced stress response, we analyzed the apoptotic response and cell cycle function in irradiated spleen cells of motheaten (me/me) mice. The defect in me/me mice has been attributed to mutations of the HCPH: gene, which encodes SHP-1. Homozygotes develop severe systemic autoimmune and inflammatory disease, whereas heterozygotes live longer and develop hematopoietic and lymphoid malignance. Spleen cells from C57BL/6 (B6)-me/me and B6-+/+ controls were analyzed after gamma-irradiation from a (137)Cs source. B6-me/me cells were significantly more resistant than B6-+/+ cells to gamma-irradiation-induced apoptosis exhibiting a higher LD(50). The defective apoptosis response of the B6-me/me cells was exhibited by T and B cells and macrophages. Of the Bcl-2 family members analyzed, a significant difference was observed in the transcription of Bax mRNA, which was up-regulated early after irradiation in B6-+/+ cells, but not B6-me/me cells. Analysis of 3,3'-dihexyloxacarbocyanine iodide revealed resistance to the gamma-irradiation-induced mitochondrial transmembrane permeability transition in the B6-me/me cells. The blocking of the cell cycle in the G(0)/G(1) phase characteristic of the irradiated B6-+/+ cells was not observed in the B6-me/me cells. There was decreased phosphorylation of p38 mitogen-activated protein kinase and increased phosphorylation of p53 from spleen cell lysates of irradiated B6-me/me mice compared with wild-type mice. These data suggest that SHP-1 plays an important role in regulation of apoptosis and cell cycle arrest after a gamma-irradiation-induced stress response.

Animals↗
PubMed2005

Deficiency of the Src homology region 2 domain-containing phosphatase 1 (SHP-1) causes enrichment of CD4+CD25+ regulatory T cells.

A subpopulation of T cells, named regulatory T cells (T(reg) cells), has been shown to play a key role in tolerance and the prevention of autoimmunity. It is not known how changes in TCR signal strength during thymic T cell development affect the generation of a T(reg) population. In this study, we took two different strategies to modulate the TCR signal strength: an intrinsic approach, where signaling was enhanced by the loss of a negative regulator, and an extrinsic approach, where signaling strength was altered through variations in the concentrations of the selecting peptide. The tyrosine phosphatase Src homology region 2 domain-containing phosphatase 1 (SHP-1) is a known negative regulator of TCR-mediated signaling. motheaten mice, lacking expression of SHP-1, showed a 2- to 3-fold increase in the percentage of CD4(+)CD25(+) T(reg) cells within the CD4(+) T cells. Similarly, the percentage of T(reg) cells was heightened in fetal thymic organ cultures (FTOCs) derived from motheaten mice compared with wild-type FTOCs, thus establishing the thymic origin of these T(reg) cells. Using FTOCs derived from DO11.10 TCR transgenic mice, we demonstrated that exposure to increasing concentrations of the cognate OVA peptide favored the appearance of T(reg) cells. Our data suggest that the development of CD4(+)CD25(+) T(reg) cells is intrinsically different from non-T(reg) cells and that T(reg) cells are selectively enriched under conditions of enhanced negative selection. Our data also reveal a key role for the SHP-1-mediated regulation of TCR signal strength in influencing the ratio of T(reg) vs non-T(reg) cells.

Animals↗
PubMed1999

Cutting edge: human 2B4, an activating NK cell receptor, recruits the protein tyrosine phosphatase SHP-2 and the adaptor signaling protein SAP.

The genetic defect in X-linked lymphoproliferative syndrome (XLP) is the Src homology 2 domain-containing protein SAP. SAP constitutively associates with the cell surface molecule, signaling lymphocytic activation molecule (SLAM), and competes with SH2-domain containing protein tyrosine phosphatase-2 (SHP-2) for recruitment to SLAM. SLAM exhibits homology with the mouse cell surface receptor 2B4. The human homologue of 2B4 has now been identified. It is recognized by the c1.7 mAb, a mAb capable of activating human NK cells. Human 2B4 became tyrosine phosphorylated following pervanadate-treatment of transfected cells and recruited SHP-2. SAP was also recruited to 2B4 in activated cells. Importantly, the 2B4-SAP interaction prevented the association between 2B4 and SHP-2. These results suggest that the phenotype of XLP may result from perturbed signaling not only through SLAM, but also other cell surface molecules that utilize SAP as a signaling adaptor protein.

Amino Acid Sequence↗
PubMed1985

Stability and utility of the unique human small cell carcinoma line SHP-77.

The human small cell (oat cell) carcinoma line, SHP-77, established by Fisher and Paulson in 1977 and originally described as a "large cell variant of oat cell cancer" has been evaluated by several different parameters and shown even after more than 200 passages to retain properties described for the original cell line. Karyotypic, histological, and biochemical features are retained, as well as tumorigenicity in nude mice. The original authors' suggestion that this is a propitious cell line for both in vitro and in vivo studies is supported by this report. Modulation of growth characteristics in vivo (in xenografts) emphasizes the plasticity of this unique line which serves as a valuable model for basic as well as therapeutic studies. SHP-77 can serve as an in vitro target in 51Cr and 111In release cytotoxicity assays as well as in in vivo nude mouse assays for evaluating immune reactivity of cells and serum from lung cancer patients. The potential histological variability of SHP-77, despite its biochemical stability, calls attention to the inadequacy of histological criteria for lung tumor classification.

Animals↗
PubMed1996

The role of protein tyrosine phosphatase SHP-1 in the regulation of IFN-gamma signaling in neural cells.

The role for protein tyrosine phosphatase SHP-1 in controlling signal transduction by IFN-gamma in astrocytes was studied. IFN-gamma induced the gamma-activated factor (GAF) within 30 min and GAF subsequently declined by 8 h after treatment. However, treatment with IFN-gamma in the presence of protein tyrosine phosphatase inhibitor vanadate blocked the decrease in GAF activity. The increased stability of GAF in vanadate-treated cultures was similarly observed in astrocytes of motheaten mice, which specifically lack the protein tyrosine phosphatase SHP-1. Prolongation of GAF activity coincided with increased expression of the IFN-inducible transcription factor, IFN-regulatory factor-1 (IRF-1). Increased IRF-1 was coincident with increased expression of MHC class I molecules in astrocytes in accordance with the activity of IRF-1 in the promoter region. These data implicate an important role for protein tyrosine phosphatases, including SHP-1, in the regulation of IFN-gamma-signaling and IFN-gamma-inducible genes in neural cells.

Animals↗
PubMed1999

Conserved residues amino-terminal of cytoplasmic tyrosines contribute to the SHP-1-mediated inhibitory function of killer cell Ig-like receptors.

The sequence I/VxYxxL, often referred to as an immunoreceptor tyrosine-based inhibition motif (ITIM), binds to the C-terminal Src homology 2 domain of the tyrosine phosphatase SHP-1. Conserved residues N-terminal of the tyrosine are not ordinarily found in other Src homology 2 domain binding motifs. The inhibitory forms of killer cell Ig-like receptors (KIR) contain two ITIMs. The role of each ITIM, and of the conserved residues upstream of the tyrosine, in the inhibition of NK cells was tested by vaccinia virus-mediated expression of mutant KIRs. Substitution of the tyrosine in the membrane-proximal ITIM abrogated the ability of KIR to block Ab-dependent cellular cytotoxicity, whereas mutation of the membrane-distal ITIM tyrosine had little effect. Substitution of the conserved hydrophobic amino acid that was located two residues N-terminal to the tyrosine weakened, but did not eliminate, the function of the receptor. In contrast, these substitutions drastically reduced the amount of SHP-1 immunoprecipitated with KIR, suggesting that weak interactions with SHP-1 may be sufficient for inhibition.

Amino Acid Sequence↗
PubMed1999

Modulation of TCR signaling by beta1 integrins: role of the tyrosine phosphatase SHP-1.

When cross-linked, beta1 integrins co-activate T cells together with a TCR-CD3 signal. Soluble anti-beta1 monoclonal antibodies, however, inhibit T cell activation. We report inhibition of early tyrosine kinases, including ZAP-70, p59(fyn), CD4-associated p56(lck) and TCR components under this condition. The tyrosine phosphatase SHP-1 is activated by engagement of beta1 integrins and is implicated in this negative regulation since no inhibition occurs in SHP-1 dominant-negative T cells. As shown by the use of Lck-deficient cells, the activation of the protein tyrosine phosphatase depends on a pool of p56(lck) that is not associated with CD4. These cross-talk events were also observed with the alpha4beta1 integrin ligand, VCAM-1. We propose that these results may be important in terms of lymphocyte circulation; while T cells migrate through the vascular endothelium, they are primed for an amplified response; as inflammation develops, a local accumulation of soluble integrin ligands may help to turn it off.

CD3 Complex↗
PubMed2006

Association between serum pepsinogens and polymorphismof PTPN11 encoding SHP-2 among Helicobacter pylori seropositive Japanese.

Helicobacter pylori (H. pylori) plays a crucial role in the development of gastric atrophy and cancer, and cagA-positive strains, which are universal in Japan, increase the risk of these outcomes substantially. The CagA protein is injected from attached H. pylori into gastric epithelial cells and undergoes Src-dependent tyrosine phosphorylation and activation of the eukaryotic phosphatase SHP-2. The CagA/SHP-2 interactions elicit cellular changes that increase the risk of carcinogenesis. We investigated the association of a frequent single nucleotide polymorphism (SNP; JST057927; G-to-A) in the PTPN11 gene that encodes SHP-2 with gastric atrophy and gastric cancer in Japan. Gastric atrophy was assessed by measuring serum pepsinogen I and II levels. The subjects comprised 454 healthy controls (126 males; mean age, 58.4) and 202 gastric cancer cases (134 males and 68 females; mean age, 66.7). All gastric cancer cases and 250 (55%) controls were H. pylori seropositive; 179 (89%) of the gastric cancer cases had gastric atrophy compared to 137 (55%) of the H. pylori seropositive controls (p < 0.001). Among HP seropositive controls compared to the common PTPN11 G/G genotype, the odds ratio of atrophy was nonsignificantly reduced with the G/A genotype (0.70; 95% CI = 0.39-1.25) and significantly reduced with the A/A genotype (0.09; 95% CI = 0.01-0.72). Lower risk for gastric atrophy had a gene-dose association with the A allele (p = 0.01, trend test). There was a clear deficiency of the A/A genotype in those with atrophy compared to those without (1 subject in the gastric atrophy group vs. 8 in the group without). Cancer cases differed from controls in frequencies of PTPN11 G/A genotype only because of a higher prevalence of atrophy among the cancer cases. The G/A SNP in the PTPN11 gene appears to be a risk factor for gastric atrophy in subjects infected with cagA-positive H. pylori. This may explain why only a proportion of CagA-positive individuals develop gastric atrophy and gastric cancer, even though infection with cagA strains is universal in Asian countries such as Japan. The functional consequences of the G/A polymorphism remain to be elucidated.

Atrophy↗
PubMed2001

Relation between the flexibility of the WPD loop and the activity of the catalytic domain of protein tyrosine phosphatase SHP-1.

The conserved WPD loop of protein tyrosine phosphatases play an important role in the catalytic activity and the invariant aspartate residue acts as a general acid/base catalyst in the dephosphorylation reaction. In our previous report, we have demonstrated that the catalytic activities of the PTPs are influenced by the flexibility and stability of the WPD loop in its active "open" conformation [Yang et al., 1998]. Phosphatases with a more flexible WPD loop generally have higher specific activity. In this report, we modify the WPD loop of SHP-1 by alanine-scan mutation of the residues flanking the loop and measure their effects on the catalytic activity of the phosphatase. We show that the S418A, V424A, S426A, E427A, and P428A mutants increase the phosphatase activity, possibly due to the increased flexibility of the WPD loop, whereas the L417A, L417G and P425A mutants decrease its phosphatase activity. In addition, we propose that the two-proline residues in the WPD loop (Pro(420) and Pro(425) in SHP-1) work as pivotal points through a conserved hydrophobic network and allows residues between the pivotal points to have maximum flexibility in enhancing the phosphatase activity. Furthermore, our data suggest that the hydrolysis of the phosphoryl-cysteine intermediate, not its formation, is the rate-limiting step with p-nitrophenyl phosphate as the substrate while both the steps are rate-limiting with phosphotyrosine as the substrate.

Alanine↗
PubMed1997

Epidermal growth factor stimulates the tyrosine phosphorylation of SHPS-1 and association of SHPS-1 with SHP-2, a SH2 domain-containing protein tyrosine phosphatase.

SHPS-1 is a 120 kDa glycosylated receptor-like protein that contains immunoglobulin-like domains in its extracellular region and four potential tyrosine phosphorylation for SH2 domain binding sites in its cytoplasmic region. Epidermal growth factor (EGF) stimulated the rapid tyrosine phosphorylation of SHPS-1 and subsequent association of SHPS-1 with SHP-2, a protein tyrosine phosphatase containing SH2 domains, in Chinese hamster ovary cells overexpressing human EGF receptors. In the cells overexpressing SHPS-1, the tyrosine phosphorylation of SHPS-1 was more evident than that observed in parent cells. However, overexpression of SHPS-1 alone did not affect the activation of MAP kinase in response to EGF. These results suggest that SHPS-1 may be involved in the recruitment of SHP-2 from the cytosol to the plasma membrane in response to EGF.

Animals↗
PubMed2000

Flt3 ligand induces tyrosine phosphorylation of gab1 and gab2 and their association with shp-2, grb2, and PI3 kinase.

The receptor tyrosine kinase Flt3 has been shown to play an important role in proliferation, differentiation, and survival of hematopoietic stem and progenitor cells. Although some postreceptor signaling events of Flt3 have been characterized, the involvement of Gab family proteins in Flt3 signaling is not known. In this study, we show that both Gab1 and Gab2 are rapidly tyrosine phosphorylated after Flt3 ligand stimulation of Flt3 ligand-responsive cells. They interact with tyrosine-phosphorylated Shp-2, p85, Grb2, and Shc. The results suggest that Gab proteins are engaged in Flt3 signaling to mediate downstream activation of Shp-2 and PI3 kinase pathways and possibly the Ras/Raf/MAPK pathway.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Suppression of SHP-2 and ERK signalling promotes self-renewal of mouse embryonic stem cells.

The propagation of pluripotent mouse embryonic stem (ES) cells depends on signals transduced through the cytokine receptor subunit gp130. Signalling molecules activated downstream of gp130 in ES cells include STAT3, the protein tyrosine phosphatase SHP-2, and the mitogen-activated protein kinases, ERK1 and ERK2. A chimaeric receptor in which tyrosine 118 in the gp130 cytoplasmic domain was mutated did not engage SHP-2 and failed to activate ERKs. However, this receptor did support ES cell self-renewal. In fact, stem cell colonies formed at 100-fold lower concentrations of cytokine than the unmodified receptor. Moreover, altered ES cell morphology and growth were observed at high cytokine concentrations. These indications of deregulated signalling in the absence of tyrosine 118 were substantiated by sustained activation of STAT3. Confirmation that ERK activation is not required for self-renewal was obtained by propagation of pluripotent ES cells in the presence of the MEK inhibitor PD098059. In fact, the growth of undifferentiated ES cells was enhanced by culture in PD098059. Thus activation of ERKs appears actively to impair self-renewal. These data imply that the self-renewal signal from gp130 is a finely tuned balance of positive and negative effectors.

Animals↗
PubMed1997

Expression, purification, and crystallization of the catalytic domain of protein tyrosine phosphatase SHP-1.

The catalytic domain of SHP-1, a SH2-domain containing protein tyrosine phosphatase, has been crystallized by the vapor diffusion method using polyethylene glycol as the precipitant. The crystals belong to the monoclinic space group P21 with unit cell dimensions a = 42.12 A, b = 87.94 A, c = 43.22 A, alpha = 90.0 degrees, beta = 120.12 degrees, and gamma = 90.0 degrees. There is one catalytic domain of SHP-1 per asymmetric unit. X-ray was diffracted to at least 2.5 A and the crystals are appropriate for high-resolution structure determination.

Binding Sites↗
PubMed1997

Regulation of cell signaling by the protein tyrosine phosphatases, CD45 and SHP-1.

An equilibrium between positive and negative regulation of immunoreceptor signaling leads to the proper execution of lymphocyte activation. Tyrosine phosphorylation is the initial event in antigen receptor-induced lymphocyte activation. It is generally accepted that protein tyrosine kinases are involved in positive regulation, whereas protein tyrosine phosphatases are important for the negative regulation of tyrosine phosphorylation-dependent processes. However, the interaction between protein tyrosine kinases and protein tyrosine phosphatases is complex. This article discusses the role of two protein tyrosine phosphatases. CD45 and SHP-1, in the regulation of immunoreceptor signaling. SHP-1 acts as a negative regulator for several immunoreceptors, including those for T- and B-cell antigen receptors. The major role of CD45 is in the positive regulation of T- and B-cell antigen receptor signaling.

Animals↗
PubMed2004

Tyrosine phosphatase activity in mitochondria: presence of Shp-2 phosphatase in mitochondria.

Tyrosine phosphorylation by unidentified enzymes has been observed in mitochondria, with recent evidence indicating that non-receptorial tyrosine kinases belonging to the Src family, which represent key players in several transduction pathways, are constitutively present in mitochondria. The extent of protein phosphorylation reflects a coordination balance between the activities of specific kinases and phophatases. The present study demonstrates that purified rat brain mitochondria possess endogenous tyrosine phosphatase activity. Mitochondrial phosphatases were found to be capable of dephosphorylating different exogenous substrates, including paranitrophenylphosphate, (32)P-poly(Glu-Tyr)(4:1) and (32)P-angiotensin. These activities are strongly inhibited by peroxovanadate, a well-known inhibitor of tyrosine phosphatases, but not by inhibitors of alkali or Ser/Thr phosphatases, and mainly take place in the intermembrane space and outer mitochondrial membrane. Using a combination of approaches, we identified the tyrosine phosphatase Shp-2 in mitochondria. Shp-2 plays a crucial role in a number of intracellular signalling cascades and is probably involved in several human diseases. It thus represents the first tyrosine phosphatase shown to be present in mitochondria.

Animals↗
PubMed2006

Age-related impairment of GM-CSF-induced signalling in neutrophils: role of SHP-1 and SOCS proteins.

Functional activities of mature human neutrophils are strongly influenced by the pro-inflammatory cytokine granulocyte macrophage-colony stimulating factor (GM-CSF). Accordingly, a defective response to GM-CSF might have dramatic consequences for neutrophil functions and the host defence against infections. Such an event is most likely to occur in senescence. A number of studies have, in fact, reported an impairment of the GM-CSF capacity to prime and/or to activate respiratory burst, as well as to delay apoptotic events, in neutrophils from elderly individuals. In the last 2 decades many efforts have been made to explore at molecular levels the mechanism underlying these defects. Recent studies let us depict a scenario in which an increased activity of inhibitory molecules, such as Src homology domain-containing protein tyrosine phosphatase-1 (SHP-1) and suppressors of cytokine signalling (SOCS), is responsible for the age-related failure of GM-CSF to stimulate neutrophil functions via inhibition of Lyn-, phosphoinositide 3-kinase (PI3-K)/extracellular signal-regulated kinase (ERK)- and signal transducers and activators of transcription (STAT)-dependent pathways. The control of SHP-1 and/or SOCS activity might therefore be an important therapeutic target for the restoration of normal immune responses during senescence.

Aging↗
PubMed2005

Bile acids reduce SR-BI expression in hepatocytes by a pathway involving FXR/RXR, SHP, and LRH-1.

Hepatic SR-BI mediates uptake of circulating cholesterol into liver hepatocytes where a part of the cholesterol is metabolised to bile acids. In the hepatocytes, bile acids reduce their own synthesis by a negative feedback loop to prevent toxic high levels of bile acids. Bile acid-activated FXR/RXR represses expression of CYP7A1, the rate-limiting enzyme during bile acid synthesis, by inducing the expression of SHP, which inhibits LXR/RXR and LRH-1-transactivation of CYP7A1. The present paper presents data indicating that CDCA suppresses SR-BI expression by the same pathway. As previously reported, LRH-1 induces SR-BI promoter activity. Here we show that CDCA or over-expression of SHP inhibit this transactivation. No FXR-response element was identified in the bile acid-responsive region of the SR-BI promoter (-1200bp/-937bp). However, a binding site for LRH-1 was characterised and shown to specifically bind LRH-1. The present study shows that also the SR-BI-mediated supply of cholesterol, the substrate for bile acid synthesis, is feedback regulated by bile acids.

Animals↗
PubMed2002

Nitration of PECAM-1 ITIM tyrosines abrogates phosphorylation and SHP-2 binding.

Platelet-endothelial cell adhesion molecule-1 (PECAM-1) is a cell adhesion molecule with a cytoplasmic immunoreceptor tyrosine-based inhibitory motif (ITIM) that, when phosphorylated, binds Src homology 2 domain-containing protein-tyrosine phosphatase (SHP-2). PECAM-1 is expressed at endothelial cell junctions where exposure to inflammatory intermediates may result in post-translational amino acid modifications that affect protein structure and function. Reactive nitrogen species (RNS), which are produced at sites of inflammation, nitrate tyrosine residues, and several proteins modified by tyrosine nitration have been found in diseased tissue. We show here that the RNS, peroxynitrite, induced nitration of both full-length cellular PECAM-1 and a purified recombinant PECAM-1 cytoplasmic domain. Mass spectrometric analysis of tryptic fragments revealed quantitative nitration of ITIM tyrosine 686. A synthetic peptide containing 3-nitrotyrosine at position 686 could not be phosphorylated nor bind SHP-2. These data suggest that ITIM tyrosine nitration may represent a mechanism for modulating phosphotyrosine-dependent signal transduction pathways.

Amino Acid Sequence↗