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At least 937 records · Page 52Linked to original sources
PubMed1997

Mouse and human SHPS-1: molecular cloning of cDNAs and chromosomal localization of genes.

SHPS-1 (SHP substrate-1) is a glycosylated receptor-like protein with three immunoglobulin-like domains in its extracellular region and four YXX(L/V/I) motifs, potential tyrosine phosphorylation and SRC homology 2 (SH2) domain binding sites, in its cytoplasmic region. Various mitogens and cell adhesion induce tyrosine phosphorylation of SHPS-1 and its subsequent association with SHP-2, and SH2 domain-containing protein tyrosine phosphatase, suggesting that SHPS-1 plays a role in cell signaling in response to both growth factors and cell adhesion. The mouse and human cDNAs encoding SHPS-1 have now been isolated. The deduced amino acid sequences of rat, human, and mouse SHPS-1 show identities of 65 to 81%. In addition to the SH2 domain binding sites, a proline-rich putative SH3 domain binding site was detected in the cytoplasmic region of SHPS-1. Northern blot analysis revealed that human SHPS-1 mRNA is most abundant in brain and that the mouse mRNA is present in embryos as early as day 7. Fluorescence in situ hybridization localized the SHPS-1 gene to human chromosome 20p13 and the F3 band of mouse chromosome 2. Furthermore, interspecific backcross analysis placed the mouse SHPS-1 locus 5.0 centimorgans distal and 1.4 centimorgans proximal to the microsatellite markers D2Mit63 and D2Mit19, respectively, in a region associated with the mutations coloboma (Cm), lethal milk (lm), and well-haarig (we).

Amino Acid Sequence↗
PubMed1998

Src family tyrosine kinases associate with and phosphorylate CTLA-4 (CD152).

CTLA-4 (CD152) transduces inhibitory signals for T cell activation. Phosphorylation and dephosphorylation of tyrosine residue (Y)-165 in the cytoplasmic region of CTLA-4 play an important role in the signal transduction and in the cell surface. While signaling molecules such as SHP-2 and the p85 subunit of PI3 kinase associate with this tyrosine residue through SH2 domains upon phosphorylation, the adapter complex AP-2 interacts with the same tyrosine when dephosphorylated, leading to clathrin-mediated endocytosis of CTLA-4. We searched for the tyrosine kinase responsible for the phosphorylation of CTLA-4. Src family tyrosine kinases Fyn, Lyn, and Lck associate with CTLA-4 and phosphorylate both Y-165 and Y-182 that are mainly responsible for interaction with Fyn through its SH2 domain. SHP-2 associates with CTLA-4, in a Fyn-dependent manner. Our observations show that src family tyrosine kinases associate with and phosphorylate CTLA-4 and thereby have an important role in the signal transduction and the endocytosis of CTLA-4.

Abatacept↗
PubMed1999

JNK/SAPK activation by platelet-derived growth factor in A431 cells requires both the phospholipase C-gamma and the phosphatidylinositol 3-kinase signaling pathways of the receptor.

Wild-type or mutant betaPDGF receptors were introduced into A431 cells that lack endogenous PDGF receptors. PDGF stimulates JNK1 activity in a dose- and time-dependent manner in cells expressing the wild-type receptor. A receptor mutant lacking all the binding sites for SHP-2, GAP, PI3K, and PLC-gamma fails to activate JNK1. Receptor mutants with no binding site for either SHP-2 or GAP can fully activate JNK1 but those which do not bind either PI3K or PLC-gamma are unable to induce JNK1 activation. PDGF-dependent JNK1 activation was reduced upon cell pretreatment with wortmannin or GF109203X and is completely abrogated by chronic PMA stimulation. Altogether, these results indicate that PDGF activates JNK1 through a pathway that involves both PI3K and PLC-gamma and subsequent activation of protein kinase C.

Androstadienes↗
PubMed2001

The requirement of tyrosines 579 and 581 for maximal ligand-dependent activation of the betaPDGFR is influenced by noncytoplasmic regions of the receptor.

Mutating tyrosines 579 and 581 of the beta platelet-derived growth factor receptor (betaPDGFR) tyrosine kinase to phenylalanines (the F2 mutation) impair activation of the receptor in response to ligand, but mutation of the analogous tyrosines in the alphaPDGFR has no effect on ligand-dependent receptor activation. We have found that the F2 mutation has only a modest effect on ligand-dependent activation of a chimeric PDGFR composed of the extracellular and transmembrane domains of the alphaPDGFR and the cytoplasmic domain of the betaPDGFR by three measures: (1) the ability to phosphorylate endogenous and exogenous protein substrates in vitro, (2) phosphorylation of tyrosine 857, and (3) binding of the effector proteins PLCgamma, RasGAP, and SHP-2. Conversely, the F2 mutation substantially impairs ligand-dependent activation of chimeric PDGFRs that consist of either the extracellular domain alone or the extracellular and transmembrane domains of the betaPDGFR and all remaining sequence from the alphaPDGFR by two measures: (1) phosphorylation of endogenous protein substrates in vitro and (2) binding of PLCgamma and SHP-2. Our results indicate that the requirement of tyrosines 579 and 581 for maximal activation of the betaPDGFR in response to ligand is primarily determined by noncytoplasmic regions of the receptor.

Animals↗
PubMed2002

Regulation of VE-cadherin linkage to the cytoskeleton in endothelial cells exposed to fluid shear stress.

Endothelial cells exposed to shear stress realigned and elongated in the direction of flow through the coordinated remodeling of their adherens junctions and actin cytoskeleton. The elaborate networks of VE-cadherin complexes in static cultures became more uniform and compact in response to shear. In contrast, the cortical actin present in static cultures was reorganized into numerous stress fiber bundles distributed parallel to the direction of flow. Exposure to shear did not significantly alter the expression of the junctional proteins VE-cadherin, beta-catenin, and alpha-catenin, but the composition of the junctional complexes did change. We detected a marked decrease in the alpha-catenin associated with VE-cadherin complexes in endothelial monolayers subjected to shear. This loss of alpha-catenin, the protein that links beta-catenin-bound cadherin to the actin cytoskeleton, was not due to decreased quantities of beta-catenin associated with VE-cadherin. Instead, the loss of alpha-catenin from the junctional complexes coincided with the increased tyrosine phosphorylation of beta-catenin associated with VE-cadherin. The change in beta-catenin phosphorylation closely correlated with the shear-induced loss of the protein tyrosine phosphatase SHP-2 from VE-cadherin complexes. Thus, the functional interaction of alpha-catenin with VE-cadherin-bound beta-catenin is regulated by the extent of tyrosine phosphorylation of beta-catenin. This, concomitantly, is regulated by SHP-2 associated with VE-cadherin complexes.

Antigens, CD↗
PubMed1999

Regulation of megakaryocytopoiesis and platelet production by tyrosine kinases and tyrosine phosphatases.

Megakaryocytopoiesis is the process by which bone marrow progenitor cells develop into mature megakaryocytes, which in turn produce platelets required for normal hemostasis. The development of this hematopoietic lineage depends on a variety of growth factors and cytokines. Growth factor-dependent tyrosine kinase receptors important in megakaryocytopoiesis include c-Kit, fibroblast growth factor receptor, the RON receptor, and the macrophage colony-stimulating factor receptor. Binding of growth factors to their respective receptors results in receptor dimerization and subsequent autophosphorylation on tyrosine residues. Tyrosine autophosphorylations become sites of association for cytoplasmic signaling molecules via their SH2 domains. Some of these molecules are themselves cytoplasmic tyrosine kinases such as the Src kinases, TEC, and CHK. Others are molecules such as phospholipase C-gamma, phosphoinositol 3-kinase, Shc, GTPase-activating protein, and the SH2-containing tyrosine phosphatases SHP-1 and SHP-2. These molecules generate second messengers, regulate the phosphorylation of other downstream molecules, and also regulate the phosphorylation of the receptor itself. The different cytoplasmic components activate pathways involved in either changes in cell growth or changes in the cytoskeleton that affect maturation of the cell. Cytokine receptors also generate signals involved in growth and differentiation. Some of these second messengers overlap with those of the receptor tyrosine kinases. Others, such as the JAKs/STATs, are involved in transcriptional control and are unique to the signaling mediated by cytokine receptors. We describe the contribution of these different signals to the growth/differentiation processes of megakaryocytes. We also describe the contribution of receptor and nonreceptor tyrosine phosphatases to these processes. Lastly, we have compiled selected methods related to the study of protein phosphorylation in megakaryocytes.

Animals↗
PubMed2000

Role of CD5 in growth regulation of B-1 cells.

CD5 is a membrane glycoprotein that is expressed on a subset of B lymphocytes called B-1 cells, thymocytes and T cells. The CD5+ B-1 cells are normally unresponsive to surface Ig receptor induced growth signals unless the CD5 gene is deleted or sequestered away. Here we show that CD5 mediated negative regulation is unique to B cell receptor (BCR) signaling. The CD5 molecule in normal B-1 cells is constitutively tyrosine phosphorylated and associates specifically with SHP-1, an SH2 domain containing protein tyrosine phosphatase. CD5 promotes a prolonged interaction between BCR and SHP-1, which may be inhibitory to BCR signaling. CD5 was shown to modulate the function of autoantibody producing B cells in transgenic mice expressing anti-DNA antibodies.

Animals↗
PubMed1981

[Measurement of the subcapsular pressure of allogeneic kidney transplants: a new method for postoperative transplant monitoring].

The results presented here show the measurement of the subcapsular hydrostatic pressure (SHP) to be a suitable method for the postoperative monitoring of a allogeneic kidney transplants. The SHP of the kidney reflects the interstitial pressure of this organ. Disturbances in the graft of immunological or non-immunological origin induce pressure increases with, for the most part, specific characteristics. An examination of the height and course of the mean subcapsular pressure level enables one to recognise and differentiate disturbances in transplant function at an early stage as well as assess their severity and duration. The results obtained so far show that the measurement of the subcapsular pressure is of particular significance in determining the extent of ischemic tubular damage, in early recognition of acute rejection and i assessing the effectiveness of immunosuppresive treatment for rejection. Repeated pressure measurements with the method described here can be performed with little technical outlay and without any stress for the patient.

Humans↗
PubMed1999

Negative regulators of cytokine signal transduction.

Enormous advances have been made over the last 10 years in unravelling cytokine signal transduction. This work has led to the recognition of the prime importance of Janus kinases (JAKs) and signal transducers and activators of transcription (STATs). More recently, the importance of negative regulators of this pathway has begun to be realised. There is now evidence for at least three families of proteins that inhibit JAK/STAT signalling. The suppressors of cytokine signalling (SOCS), protein inhibitors of activated STATs (PIAS) and the SH2-containing phosphatase (SHP-1). This review describes some of the key features of SOCS proteins and contrasts their actions with other negative regulators, the PIAS proteins and SHP-1.

Animals↗
PubMed2001

Insulin inhibits leptin receptor signalling in HEK293 cells at the level of janus kinase-2: a potential mechanism for hyperinsulinaemia-associated leptin resistance.

AIMS/HYPOTHESIS: Leptin resistance in obese humans seems to be predominantly caused by signalling abnormalities at the post receptor level. Leptin resistance in obese individuals is frequently associated with insulin resistance and pronounced hyperinsulinaemia indicating a negative crosstalk of the insulin and leptin signalling chain. METHODS: This hypothesis was tested using a cell model of peripheral leptin signalling, i. e. insulin-secreting cell lines (RINr1046-38). Mechanisms for a crosstalk between the insulin and leptin signalling pathway were also studied in rat-1 and HEK293 cells overexpressing elements of the insulin and leptin signalling chain. RESULTS: The effects of leptin on insulin secretion are completely cancelled by a 4-h preincubation with 1 nmol/l insulin, supporting the hypothesis of a negative crosstalk of insulin and leptin signalling. We investigated the potential molecular mechanisms in more detail in HEK293 cells and Rat-1 fibroblasts that overexpressed proteins of the insulin and leptin signalling chain. Leptin (60 ng/ml) stimulated autophosphorylation of JAK-2 in HEK 293 cells. This leptin effect could be inhibited by simultaneous treatment of cells with insulin. Furthermore, overexpression of the insulin receptor in HEK 293 cells clearly reduced JAK-2 phosphorylation and led further downstream to a diminished phosphatidylinositol 3-kinase activity. The inhibitory effect of the insulin signal could be partially prevented by transfection of the cells with an inactive mutant of the tyrosine phosphatase SHP-1. CONCLUSION/INTERPRETATION: In summary, our data suggest that the insulin receptor signalling pathway interferes with leptin signalling at the level of JAK-2. Inhibition of JAK-2 phosphorylation might occur through SHP-1-dependent pathways, indicating that hyperinsulinaemia contributes to the pathogenesis of leptin resistance.

Animals↗
PubMed2006

A simple preparation method of crystals of soybean hull peroxidase.

Soybean hull peroxidase (SHP) was crystallised from an enzyme solution with low purity by a simple method. The enzyme solution was purified by cooperation salting out of acetone and ammonium sulphate, and lumpy crystals were obtained with the size of about 40 x 30 mum when ammonium sulphate was quickly added to the enzyme solution. The crystal was examined and confirmed to be an SHP crystal by the method of activity test. The result shows that, though the purity of the enzyme solution was not high, crystals could be formed when the enzyme solution rapidly reached to a degree of supersaturation, which was different from the traditional methods of protein crystallisation. Additionally, a purification method of acetone and ammonium sulphate fractional salting out was also studied, in which the procedure was simplified, and a satisfactory purification effect was obtained.

Acetone↗
PubMed1999

Clinical outcome of Schönlein-Henoch purpura nephritis in children.

We studied the long-term outcome of 64 children with biopsy-proven Schönlein-Henoch purpura (SHP) nephritis over 1-23 years of follow-up. Overall renal survival 10 years after onset was 73%. Multivariate logistic regression analysis identified initial renal insufficiency (P=0.004), nephrotic syndrome (P=0.037), and the severity of histological alterations, as defined by the proportion of glomerular crescents (P=0.051), as significant independent predictors of progressive renal failure. Four patients followed for more than 19 years showed glomerular damage after transient recovery. Eight children with crescentic nephritis associated with a rapidly progressive course and/or persistent nephrotic syndrome were treated by at least seven sessions of plasma exchange (PE) within 16 weeks of onset of purpura. During treatment serum creatinine levels dropped in each patient from a mean of 2.3 to 1.1 mg/dl, followed by a rebound increase. Repeated courses of PE in 5 patients produced comparable responses. Four patients undergoing PE reached end-stage renal disease at 1.2.-3.7 years after onset, whilst 3 finally were in preterminal renal failure (creatinine 3.2-6.1 mg/dl after 7-13.5 years), and 1 patient reached a normal glomerular filtration rate. Our experience suggests that initial renal insufficiency is the best single predictor of the further clinical course in children with SHP nephritis. Early PE appears to delay the progression in some patients with severe, rapidly progressive forms of the disease.

Adolescent↗
PubMed2004

Helicobacter pylori CagA protein variation associated with gastric cancer in Asia.

Recent molecular analysis has provided the pathological actions of CagA on gastric epithelial cells. CagA is injected into epithelial cells via the type IV secretion system and undergoes tyrosine phosphorylation in the cells. In addition, translocated CagA forms a physical complex with SHP-2. There are two major CagA subtypes; the East Asian and the Western type. The East Asian CagA protein possesses stronger SHP-2 binding activity than the Western CagA. The grades of inflammation, activity of gastritis, and atrophy are significantly higher in gastritis patients infected with the East Asian CagA-positive strain than in gastritis patients infected with the cagA-negative or Western CagA-positive strains. The prevalence of the East Asian CagA-positive strain is associated with the mortality rate of gastric cancer in Asia. Endemic circulation of H. pylori populations carrying biologically more active CagA proteins in East Asian countries, where the mortality rate of gastric cancer is among the highest in the world, may be involved in increasing the risk of gastric cancer in these populations.

Amino Acid Sequence↗
PubMed1989

Expression of a cytochrome c2 isozyme restores photosynthetic growth of Rhodobacter sphaeroides mutants lacking the wild-type cytochrome c2 gene.

Deletion of the cytochrome c2 gene in the purple bacterium Rhodobacter sphaeroides renders it incapable of phototrophic growth (strain cycA65). However, suppressor mutants which restore the ability to grow phototrophically are obtained at relatively high frequency (1-10 in 10(7)). We examined two such suppressors (strains cycA65R5 and cycA65R7) and found the expected complement of electron transfer proteins minus cytochrome c2: SHP, c', c551.5, and c554. Instead of cytochrome c2 which elutes from DEAE-cellulose between SHP and cytochrome c', at about 50 mM ionic strength in wild-type extracts, we found a new high redox potential cytochrome c in the mutants which elutes with cytochrome c551.5 at about 150 mM ionic strength. The new cytochrome is more acidic than cytochrome c2, but is about the same size or slightly smaller (13,500 Da). The redox potential of the new cytochrome from strain cycA65R7 (294 mV) is about 70 mV lower than that of cytochrome c2. The 280 nm absorbance of the new cytochrome is smaller than that of cytochrome c2, which suggests that there is less tryptophan (the latter has two residues). In vitro kinetics of reduction by lumiflavin and FMN semiquinones show that the reactivity of the new cytochrome is similar to that of cytochrome c2, and that there is a relatively large positive charge (+2.6) at the site of reduction, despite the overall negative charge of the protein. This behavior is characteristic of cytochromes c2 and unlike the majority of bacterial cytochromes examined. Fourteen out of twenty-four of the N-terminal amino acids of the new cytochrome are identical to the sequence of cytochrome c2. The N-termini of the cycA65R5 and cycA65R7 cytochromes were the same. The kinetics and sequence data indicate that the new protein may be a cytochrome c2 isozyme, which is not detectable in wild-type cells under photosynthetic growth conditions. We propose the name iso-2 cytochrome c2 for the new cytochrome produced in the suppressor strains.

Amino Acid Sequence↗
PubMed2006

Hepatocyte nuclear factor-4alpha plays pivotal roles in the regulation of mouse carboxylesterase 2 gene transcription in mouse liver.

The mouse carboxylesterase 2 isozyme, mCES2, is thought to play important roles in lipid metabolism and is expressed in the liver, kidney, and small intestine at high levels. In this study, we examined the molecular mechanisms controlling this tissue-specific expression of mCES2, and demonstrated that hepatocyte nuclear factor-4alpha (HNF-4alpha) could enhance transcription of the mCES2 gene in vitro and in vivo. It was found that effects of HNF-4alpha on the level of mCES2 promoter activity were repressed by small heterodimer partner (SHP) and chenodeoxycholic acid (CDCA) in luciferase assays. Accordingly, mCES2 gene transcription was repressed by CDCA treatment in mouse immortalized hepatocytes. Our results suggested that this repression resulted from the combined effects of both inhibition of HNF-4alpha transactivation ability by SHP and reduction of HNF-4alpha expression level. These findings show that HNF-4alpha plays an important role in the regulation of mCES2 gene transcription.

Animals↗
PubMed2003

9.1C3 is identical to LAIR-1, which is expressed on hematopoietic progenitors.

The leukocyte-associated Ig-like receptor-1 (LAIR-1) is a negative regulator of natural killer (NK) cells, its encoding gene belonging to the leukocyte receptor complex (LRC). Antibody to LAIR-1 can inhibit Ab-induced redirected lysis and TNF-alpha release of effector cells. LAIR-1 contains 2 immunoreceptor tyrosine-based inhibitory motifs (ITIM) in its cytoplasmic region that have been shown to bind constitutively and presumably regulate the tyrosine phosphatase SHP-1 in hematopoietic cells. SHP-1 mutation in mice results in abnormal lymphoproliferation, suggesting that LAIR-1 may also be implicated in regulating hematopoiesis. Here we investigated a monoclonal antibody, 9.1C3, against a NK cell antigen previously described as inducing increased colony formation in in vitro assays of human bone marrow cells. We found that 9.1C3 was expressed on CD34 positive hematopoietic progenitors for the first time. In functional assays, 9.1C3 MAb was able to inhibit Ab-induced redirected lysis and TNF-alpha secretion of NK cells. We proved that 9.1C3 is identical to LAIR-1, based on the fact that not only the antigen precipitated by 9.1C3 MAb was of 40kDa but also 9.1C3 MAb bound specifically to LAIR-1 cDNA transfected COS7 cells as well as recognized LAIR-1 fusion protein in ELISA. This finding provided the first evidence that LAIR-1 expresses on hematopoietic progenitor, implicating its role in the regulation of hematopoiesis at early stage.

Animals↗
PubMed2004

IgSF13, a novel human inhibitory receptor of the immunoglobulin superfamily, is preferentially expressed in dendritic cells and monocytes.

A novel inhibitory receptor of immunoglobin superfamily (IgSF), IgSF member 13 (IgSF13), has been identified from human dendritic cells (DC). IgSF13 is a type I transmembrane protein containing an N-terminal signal peptide, a extracellular region with a single Ig V-like domain, a transmembrane region, and a cytoplasmic tail with two classical immunoreceptor tyrosine-based inhibitory motifs (ITIM), suggesting its inhibitory function. IgSF13 shows significant homology to human CMRF35 and pIgR. IgSF13 gene is mapped to chromosome 17q25.2, very close to that of CMRF35. IgSF13 is preferentially expressed in myelo-monocytic cells, including monocytes, monocyte-derived DC, and monocyte-related cell lines. Upon pervanadate treatment, IgSF13 was hyper-phosphorylated and associated with Src homology-2 domain-containing phosphatases SHP-1 and SHIP, but not SHP-2. The identification of IgSF13 as a novel ITIM-bearing receptor selectively expressed by DC and monocytes suggests that it may be potentially involved in the negative regulation of specific leukocyte population.

Amino Acid Sequence↗
PubMed2004

Ligand stimulation of CD155alpha inhibits cell adhesion and enhances cell migration in fibroblasts.

CD155 (poliovirus receptor) localizes in cell-matrix adhesions and cell-cell junctions, but its role in the regulation of cell adhesion and cell motility has not been investigated. We identified a conserved immunoreceptor tyrosine-based inhibitory motif (ITIM) in the cytoplasmic domain of human CD155alpha. The ITIM was tyrosine-phosphorylated upon binding of anti-CD155 monoclonal antibody D171, poliovirus, and DNAM-1 (CD226) to human CD155alpha, and recruited SH2-domain-containing tyrosine phosphatase-2 (SHP-2). After CD155alpha stimulation with its ligands, cell adhesion was inhibited and cell motility was enhanced, effects that were associated with the phosphorylation of ITIM by Src kinases and accompanied by dephosphorylation of focal adhesion kinase and paxillin. These effects were abolished by introducing a point-mutation in Y398F into the ITIM of CD155alpha and by coexpression of a dominant negative SHP-2 mutant with CD155alpha. These results suggest that CD155alpha plays a role in the regulation of cell adhesion and cell motility.

Amino Acid Sequence↗