Ptpn6

..autoantibodies (AAb), we compared the genetic and structural characteristics of IgM AAb from autoimmune prone motheaten (mev) mice with natural autoantibodies (NAAb) from normal background C57/BL6 strain...

..a substrate of SHP-1 in vitro and is hyperphosphorylated on tyrosine in SHP-1 deficient macrophages from viable-motheaten mice...

..of SHP-1 on TCR-mediated apoptosis by assaying the sensitivity of peripheral T cells from SHP-1-deficient viable motheaten (mev) mice to cell death following TCR restimulation...

Mice homozygous for the viable motheaten (Hcph(me-v)) mutation are deficient in SHP-1 protein-tyrosine phosphatase, resulting in severe systemic autoimmunity and immune dysfunction...

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..Importantly, the human gene maps to chromosome 12 region p12-p13. This region is associated with rearrangements in approximately 10% of cases of acute lymphocytic leukemia in children...

The murine "motheaten" (me) mutation has been bred onto the NFS background and combined with the X-linked immunodeficiency (xid) mutation to investigate the effect of the xid-induced B cell maturational block on the widespread ..

..Taken together, these findings indicate that SHPS-1 is likely to play a significant role in macrophages, at least partially as a consequence of its capacity to recruit SHP-1...

..murine Dominant white spotting (W) locus and the Shp1 protein tyrosine phosphatase, the product of the murine motheaten (me) gene...

Mice homozygous for the recessive allelic mutation motheaten (me) or viable motheaten (mev) on chromosome 6 develop severe defects in hematopoiesis...

..Mutations at the 'motheaten' locus result in severe immunological dysfunction due to disruption of the structural gene encoding Src-homology ..

b>Motheaten viable (mev) mice are deficient in the cytosolic protein tyrosine phosphatase, PTP1C, and exhibit severe B cell immunodeficiency and autoantibody production...

Mice that are homozygous for the autosomal recessive motheaten allele (me/me) lack the protein tyrosine phosphatase SHP-1...

..These two additional members of the PTPase family accentuate the variety of PTPase structures and indicate the potential diversity of function for intracellular tyrosine phosphatases...

Mice with the recessive motheaten (me) or the allelic viable motheaten (mev) mutations express a severe autoimmune and immunodeficiency syndrome...

Spontaneous loss-of-function mutations in the protein-tyrosine phosphatase Shp1 cause the motheaten phenotype, characterized by widespread inflammation and autoimmunity...

..between the RTK c-Kit, encoded at the W locus, and the SH2-containing non-transmembrane PTP SHP1, encoded at the motheaten (me) locus (1)...

..containing a COOH-terminal catalytic and two NH2-terminal Src homology 2 (SH2) domains, have been identified in motheaten (me) and viable motheaten (mev) mice and are associated with severe hemopoietic dysregulation...

..These results emphasize that SHP1 as a part of different signaling pathways plays an important role in the global regulation of astrocytic and microglial activation in the normal and injured CNS...

A new spontaneous autosomal recessive mutation has recently occurred at the motheaten (me) locus on Chromosome 6 in strain C57BL/6J mice...

..It remains to be determined what the basic deficiency in me/me mice is and whether it affects primarily B cells or all lymphoid cells...

Mice homozygous for the motheaten (Hcphme) or viable motheaten (Hcphme-v) mutations are deficient in functional SHP-1 protein-tyrosine phosphatase and show severe defects in hematopoiesis...

..express the protein tyrosine phosphatase SHP-1 and that myelin formation was decreased in SHP-1-deficient motheaten mice compared to that in normal littermates...

A new recessive mutation, motheaten (me), is on chromosome 6, 21.9 +/- 4.3 recombination units distal to white (Miwh)...

..mature osteoclasts were generated from protein tyrosine phosphatase Src homology 2-domain phosphatase-1-defective Hcph(me-v)/Hcph(me-v) (me(v)/me(v)) bone marrow cells in the presence of M-CSF and LPS without addition of RANKL in ..

..These results indicate that activated microglia may participate in determining whether neurons in AVCN live or die following deafferentation...

..This suggests that PTPs are involved in the regulation of growth and differentiation during preimplantation development...

..Thus, we define a new family of myeloid receptors, and demonstrate that the first member of this family, CLM-1, is an inhibitory receptor, able to block osteoclastogenesis...

..These results demonstrate that SHP-1 acts to negatively regulate IL-3-driven survival and proliferation, potentially via regulation of tyrosine phosphorylation of Aic2A and STAT5...

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..Together, these data show that TGF-beta1 suppresses IFN-gamma signaling and transcriptional responses in CD4+ T cells through the PTP Shp-1...

..Here, we describe a lactation defect that severely limits the use of one of the most commonly used MMTV-Cre founder lines...

..survival, and functional responses to stimulation using bone marrow-derived mast cells from viable motheaten (mev) mice...

..Our results show that SHP-1 is an essential mediator of endorepellin activity and discover a novel functional interaction between the integrin alpha2 subunit and SHP-1...

..Subsequently, the expression patterns of 11 PTPs (TC-PTP, PTP1C, PTP1D, PTP-MEG2, PTP-PEST, RPTPJ, RPTPε, RPTPRR, RPTPσ, RPTPκ and RPTPγ) were further analyzed in detail in ..

..These findings suggest that SHP1/2 activity in the hippocampus is involved in the control of contextual fear extinction...

..The same mechanism for malignant transformation seems to be operative in other human lymphoid and myeloid malignancies. Thus, PLC-beta3 is likely a tumor suppressor...

..The most pragmatic aspect of our findings is that successful therapeutic inhibition of c-Src, in the context of the osteoclast, will require its stringent targeting...

..how SHP-1 regulates mast cell signaling, we established bone marrow-derived mast cells from SHP-1-deficient motheaten and wild-type mice and analyzed downstream signals induced by cross-linking of high affinity IgE receptor, Fc ..

..Specifically, T cells from the SHP-1-deficient mouse, motheaten, exhibit a hyperproliferative phenotype when activated by cognate peptide-pulsed APCs...

..Here we show that Ptpn6(me-v/me-v) (also known as viable motheaten) mice bearing a functionally deficient SHP-1 protein are markedly glucose tolerant and insulin sensitive as ..

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Viable motheaten mutant mice (abbreviated allele symbol me(v)) are deficient in Src-homology 2-domain phosphatase (SHP)-1, a critical negative regulator of signal transduction in hematopoietic cells...

..In conclusion, our results indicate that Cdk2-associated complexes, by targeting SHP-1 for proteolysis, counteract the ability of SHP-1 to block cell cycle progression of IECs...

..Collectively, our data reveal SHP-1 as a critical modifier of Treg function and a potential therapeutic target for augmenting Treg-mediated suppression in certain disease states...

..A similar NK cell phenotype is observed in viable motheaten (mev) mice, which show reduced SHP-1 activity due to a mutation in the Shp-1 gene...

..analysis of T cell development in H-Y TCR transgenic mice rendered SHP-1 deficient by introduction of the viable motheaten mutation or a dominant negative SHP-1-encoding transgene...

We have studied the hematopoietic system of the immunodeficient mouse mutant, viable motheaten (mev/mev). These mice usually die by 9 weeks of age from severe pneumonitis...

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..These results indicate the particular sensitivity of this model for efficacy of potentially new therapeutic but non-cytostatic compounds for clinical use...

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..as demonstrated by the heightened growth responses to hematopoietic growth factors in hematopoietic cells of motheaten mice, which lack functional SHP-1 expression due to mutations in the SHP-1 gene...

In mice homozygous for the 'viable motheaten' (mev) mutation, numbers of macrophage progenitor cells, particularly monocytes, were markedly increased in the bone marrow and spleen...

..cell phosphatase (HCP) underlies severe hematopoietic and immunologic abnormalities in mice homozygous for the motheaten and viable motheaten mutations...

..on the T cell phenotype and apoptosis function in hematopoietic cell protein-tyrosine phosphatase-deficient motheaten mice...

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Mice homozygous for the recessive mutation motheaten (me) are deficient in capacity for immune response but show an elevated level of serum immunoglobulins...

b>Motheaten mice have a mutation that causes abnormal splicing of the SHP-1 gene producing transcripts that are out of frame. Thus, motheaten mice cannot produce normal SHP-1 protein...

Hematopoietic cell phosphatase (Hcph) was identified by amplification of conserved protein tyrosine phosphatase sequences from a myeloid cell line and is predominantly expressed in hematopoietic cells...

..mutations of the Src homology 2 (SH2) domain-containing tyrosine phosphatase 1 (SHP-1) in mice give rise to the motheaten (me) phenotype...

..were determined using indirect immunofluorescence microscopy of epidermal whole mounts taken from viable motheaten (mev), nude (nu), and rhino (rhhr) mice...

..activities induced by chemokines, we examined the role of SHP-1 in functions of chemokines using viable motheaten (me(v)/me(v)) mice that were deficient in SHP-1...

..loci that reduce NK-cell activity in the homozygous state were identified, including beige (bg), hairless (hr), motheaten (me), obese (ob), steel (Sl) and, to lesser extent, dominant spotting (W)...

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b>Motheaten mice have normal levels of T lymphocytes but reduced levels of B lymphocytes...

Bone marrow cells from viable motheaten (me(v)) mutant mice fail to repopulate the thymus of irradiated recipients upon i.v. adoptive transfer...

..This may reflect intrinsic differences between human and rodent physiology as well as increased technical difficulties in performing glucose clamps in mice...

..These data reveal a novel ITAM-mediated inhibitory signaling pathway in DCs triggered by MHC II engagement of LAG-3, providing a molecular mechanism in which regulatory T cells may suppress via modulating DC function...

..we sought to define the function of SHP-1 in the lung by characterizing the pulmonary inflammation of viable motheaten (mev) mice, and to investigate the molecular mechanisms involved...

..In this paper, two murine mutant mice viable motheaten and osteopetrosis are analyzed...

..We conclude that the proposed central role of SHP in cholesterol metabolism is based on a two-step mechanism that is dependent on both coactivator competition and direct transcriptional repression...

..In vivo, Leishmania major infection, which footpad inflammation is mostly undetectable in SHP-1-deficient viable motheaten mice, was accompanied by increased inducible nitric oxide synthase and activation of neutrophils...

..however, implied by the overexpansion and inappropriate activation of granulocyte populations in SHP-1-deficient motheaten (me/me) and motheaten viable (me(v)/me(v)) mice...

..These data demonstrate that the level of SHP-1 plays an important role in regulating the activation threshold of autoreactive T cells...

..Moreover, its expression is not restricted to natural killer cells, as reported for the majority of group V lectins. Nkcl is expressed in pluripotent myeloid precursors, precursor and mature macrophages, and neutrophils...

..In the present study, we derived two pre-B cell lines, PBCL-1 and PBCL-2, from normal and SHP-1-deficient motheaten mice, respectively, and characterized hyperphosphorylated proteins in PBCL-2 cells to identify SHP-1-regulated ..

..These findings suggest that a new pair of ITIM/ITAM-bearing receptors, LMIR1 and 2, regulate mast cell-mediated inflammatory responses through yet to be defined ligand(s)...

..Therefore, SHP-1 plays a role in signals downstream of RANKL by recruitment to the complex containing TRAF6 and these observations may help to understand the mechanism of osteoporosis in Me(v)/Me(v) mice...

..mutation did not affect IL-4-induced STAT6 phosphorylation in differentiated Th1 cells derived from viable motheaten (me(v)/me(v)) mice. These results led us to focus on a novel mechanism...

..The viable motheaten (Hcphme-v) mutant mice (mev) suffer from progressive inflammation due to a deficiency of SHP-1 enzyme activity [..

..Thr(72) in macrophages derived from mice homozygous for the motheaten viable (me-v) allele of the hemopoietic cell phosphatase (Hcph) gene...

..The rapid, growth factor-induced tyrosine phosphorylation of PTP-1C suggests that it may be involved in very early events in growth factor signal transduction...

..coli phagocytosis. Thus, by binding FcgammaRIII, E. coli triggers an inhibitory FcRgamma pathway that both impairs MARCO-mediated bacterial clearance and activates TNF-alpha secretion...

..e. upstream of exon 1) have predominantly hepatic promoter activity and the 5'-flanking sequences of the major small intestine mRNA (i.e. upstream of exon 4) have preferential intestinal promoter activity.(ABSTRACT TRUNCATED AT 400 WORDS)..

..Fourth, circumvention of the toleragenic mechanism might be used to prevent normal gestation, leading to termination of pregnancy within a few days following implantation of the blastocyst. ..

..The viable motheaten mutation results in severe SHP- 1 deficiency and provides a critical tool for elucidating the mechanism of ..

..Because it is clear that innate immunity is degenerate in that individual proteins frequently offer broad defense against bacterial, viral, and fungal pathogens, these studies will yield insight into innate immune mechanisms at large. ..

..In the case of mutations that abolish LPS tolerance, we will attempt to determine the net impact on host resistance to infection. ..

..The new mutations that are found--and those that have already been found in preliminary efforts--will be isolated by positional cloning. ..

..We believe that information gained under these specific aims will elucidate mechanisms whereby SHP-1 controls virus infections in oligodendrocytes and perhaps other cells of the CNS. ..

..This work will enrich our understanding of how and why infections are sometimes lethal. ..

..abstract_text> ..

..Lps/n, the common wild-type Lps allele; Tlr4/Lps-d, the Lps/d allele of Tlr4; Tlr4/Lps-n, the Lps/n allele of Tlr4. ..

..Mice genetically deficient in SHP- I (motheaten and viable motheaten mice) have a dramatically increased susceptibility to the attenuated BeAn strain of Theiler'..

..The present project is thus focused on defining the essential role of SHP-1 in macrophage-mediated demyelinating disease. ..