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At least 253 records · Page 14Linked to original sources
PubMed1997

Protein-tyrosine phosphatase SHP-1 is dispensable for FcgammaRIIB-mediated inhibition of B cell antigen receptor activation.

The inhibitory Fc receptor, FcgammaRIIB, provides a signal that aborts B cell antigen receptor activation, blocking extracellular calcium influx. Because the protein-tyrosine phosphatase SHP-1 binds tyrosyl phosphorylated FcgammaRIIB and FcgammaRIIB-mediated inhibition is defective in motheaten (me/me) mice, which do not express SHP-1, it was proposed that SHP-1 mediates FcgammaRIIB signaling in B cells (D'Ambrosio, D., Hippen, K. L., Minskoff, S. A., Mellman, I., Pani, G., Siminovitch, K. A., and Cambier, J. C. (1995) Science 268, 293-297). However, SHP-1 is dispensable for FcgammaRIIB-mediated inhibition of FcepsilonRI signaling in mast cells (Ono, M., Bolland, S., Tempst, P., and Ravetch, J. V. (1996) Nature 383, 263-266), prompting us to re-examine the role of SHP-1 in FcgammaRIIB signaling in B cells. We generated immortalized sIgM+, FcgammaRIIB+ cell lines from me/me mice and normal littermates. Co-ligation of FcgammaRIIB and the sIgM antigen receptor inhibits calcium influx in both cell lines. Inhibition is reversed by preincubation with anti-FcgammaRIIB antibodies, indicating that it is mediated by FcgammaRIIB. The inositol 5' phosphatase SHIP is recruited to tyrosyl-phosphorylated FcgammaRIIB in both cell lines. FcgammaRIIB-mediated CD19 dephosphorylation also occurs in the presence or the absence of SHP-1. Our results establish that SHP-1 is dispensable for FcgammaRIIB-mediated inhibition of sIgM antigen receptor signaling.

Animals↗
PubMed1998

Structure and expression of the orphan nuclear receptor SHP gene.

To determine the organization of the orphan nuclear receptor SHP gene (Seol, W., Choi, H.-S., and Moore, D.D. (1996) Science 272, 1336-1339), genomic clones were isolated from human and mouse genomic libraries. The SHP gene was composed of two exons interrupted by a single intron spanning approximately 1.8 kilobases in human and 1.2 kilobases in mouse. Genomic Southern blot analysis and fluorescence in situ hybridization of human metaphase chromosomes indicated that the SHP gene is located at the human chromosome 1p36.1 subband. The 5'-flanking regions of human and mouse SHP genes were highly conserved, showing 77% homology in the region of approximately 600 nucleotides upstream from the transcription start site. Primer extension analysis was carried out to determine the transcription start site of human SHP to 32 nucleotides downstream of a potential TATA box. The human SHP gene was specifically expressed in fetal liver, fetal adrenal gland, adult spleen, and adult small intestine. As expected from this expression pattern, the activity of the mouse SHP promoter measured by transient transfection was significantly higher in the adrenal-derived Y1 cells than HeLa cells.

Animals↗
PubMed1998

Protein-tyrosine phosphatase Shp-2 regulates cell spreading, migration, and focal adhesion.

Shp-2, a widely expressed cytoplasmic tyrosine phosphatase with two SH2 domains, is believed to participate in signal relay downstream of growth factor receptors. We show here that this phosphatase also plays an important role in the control of cell spreading, migration, and cytoskeletal architecture. Fibroblast cells lacking a functional Shp-2 were impaired in their ability to spread and migrate on fibronectin compared with wild-type cells. Furthermore, Shp-2 mutant cells displayed an increased number of focal adhesions and condensed F-actin aggregation at the cell periphery, properties reminiscent of focal adhesion kinase (FAK)-deficient cells. This is consistent with our previous observations in vivo that mice homozygous for the Shp-2 mutation died at midgestation with similar phenotype to FAK and fibronectin-deficient embryos, having severe defects in mesodermal patterning, particularly the truncation of posterior structures. Biochemical analysis demonstrated that FAK dephosphorylation was significantly reduced in Shp-2 mutant cells in suspension. Furthermore, regulated association of Src SH2 domain with FAK and paxillin during cell attachment and detachment on fibronectin was disrupted in Shp-2 mutant cells. This report defines a unique role of the Shp-2 tyrosine phosphatase in cell motility, which might guide the design of a new strategy for pharmaceutical interference of tumor metastasis.

Animals↗
PubMed1998

The Shp-2 tyrosine phosphatase has opposite effects in mediating the activation of extracellular signal-regulated and c-Jun NH2-terminal mitogen-activated protein kinases.

Shp-2 is a widely expressed cytoplasmic tyrosine phosphatase with two SH2 domains. A targeted mutant allele of the Shp-2 gene with a deletion of 65 amino acids in the NH2-terminal SH2 domain was created that leads to embryonic lethality at mid-gestation in homozygous mutant mice. To define the Shp-2 function in cell signaling, we have established mutant fibroblast cell lines, and have examined the effect of the Shp-2 mutation on extracellular signal-regulated kinase (ERK) and c-Jun NH2-terminal kinase (JNK) mitogen-activated protein (MAP) kinase pathways. Insulin-like growth factor (IGF)-I-induced ERK activation was completely abolished, while ERK activity upon platelet-derived growth factor and epidermal growth factor stimulation was significantly reduced and shortened in mutant cells. Stimulation of ERK by phorbol 12-myristate 13-acetate was not affected in mutant cells, but the phorbol 12-myristate 13-acetate-induced ERK activity decayed much faster compared with that in wild-type cells. In contrast, JNK activation upon heat shock was significantly enhanced in Shp-2 mutant cells. Based on these results, we conclude that Shp-2 plays differential positive regulatory roles in various mitogenic signaling pathways leading to ERK activation, and that Shp-2 is a negative effector in JNK activation by cellular stress. This is the first evidence that a tyrosine phosphatase has opposite effects in mediating the activation of ERK and JNK MAP kinases.

Animals↗
PubMed1999

Definition of the sites of interaction between the protein tyrosine phosphatase SHP-1 and CD22.

CD22 phosphorylation is an early event of B cell antigen receptor engagement and results in the recruitment of the negative regulatory tyrosine phosphatase, SHP-1. Peptides representing the potential phosphorylation sites within the cytoplasmic domain of CD22 have been used to stimulate SHP-1 catalytic activity and to inhibit the binding of SHP-1 to CD22 (Doody, G., Justement, L., Delibrias, C., Matthews, R., Lin, J., Thomas, M., and Fearon, D. (1995) Science 269, 242-244). However, the sites of phosphorylation within the cytoplasmic domain of CD22 and the importance of each for the recruitment and activation of SHP-1 remain unknown. Here we demonstrate that there are multiple sites within the cytoplasmic domain of CD22 that interact with the Src homology 2 domains of SHP-1. Nevertheless, a minimum of two tyrosines in CD22 is required for the association with SHP-1. Furthermore, both Src homology 2 domains of SHP-1 are necessary for efficient binding to CD22.

Amino Acid Sequence↗
PubMed2000

Requirement for protein-tyrosine phosphatase SHP-2 in insulin-induced activation of c-Jun NH(2)-terminal kinase.

Mitogen-activated protein kinases, including extracellular signal-regulated kinases and c-Jun NH(2)-terminal kinases (JNKs), are activated by insulin. Although the mechanism by which the insulin receptor activates extracellular signal-regulated kinases is relatively well defined, the pathway that leads to JNK activation is poorly understood. Overexpression of a catalytically inactive mutant (SHP-2C/S) of the protein-tyrosine phosphatase SHP-2 in Rat-1 fibroblasts that also express human insulin receptors has now revealed that activation of JNKs by insulin and epidermal growth factor, but not that by anisomycin or sorbitol, requires SHP-2. A dominant negative mutant (RasN17) of Ha-Ras blocked insulin-induced JNK activation, whereas a dominant negative mutant (RacN17) of Rac1 or a specific inhibitor (LY294002) of phosphoinositide 3-kinase did not, indicating a role for Ras, but not for Rac or phosphoinositide 3-kinase, in this effect. SHP-2C/S markedly inhibited Ras activation in response to insulin without affecting insulin-induced tyrosine phosphorylation of cellular substrates or the dissociation of the Crk-p130(Cas) complex. In contrast, SHP-2C/S did not inhibit activation of JNKs induced by a constitutively active mutant (RasV12) of Ha-Ras. Furthermore, expression of myristoylated SOS, which functions as a potent activator of Ras, induced JNK activation even when SHP-2 was inactivated. These results suggest that SHP-2 contributes to JNK activation in response to insulin by positively regulating the Ras signaling pathway at the same level as, or upstream from, SOS.

Animals↗
PubMed2000

Dissecting the interaction of SHP-2 with PZR, an immunoglobulin family protein containing immunoreceptor tyrosine-based inhibitory motifs.

Tyrosine phosphorylation of membrane proteins plays a crucial role in cell signaling by recruiting Src homology 2 (SH2) domain-containing signaling molecules. Recently, we have isolated a transmembrane protein designated PZR that specifically binds tyrosine phosphatase SHP-2, which has two SH2 domains (Zhao, Z. J., and Zhao, R. (1998) J. Biol. Chem. 273, 29367-29372). PZR belongs to the immunoglobulin superfamily. Its intracellular segment contains four putative sites of tyrosine phosphorylation. By site-specific mutagenesis, we found that the tyrosine 241 and 263 embedded in the consensus immunoreceptor tyrosine-based inhibitory motifs VIYAQL and VVYADI, respectively, accounted for the entire tyrosine phosphorylation of PZR. The interaction between PZR and SHP-2 requires involvement of both tyrosyl residues of the former and both SH2 domains of the latter, since its was disrupted by mutating a single tyrosyl residue or an SH2 domain. Overexpression of catalytically inactive but not active forms of SHP-2 bearing intact SH2 domains in cells caused hyperphosphorylation of PZR. In vitro, tyrosine-phosphorylated PZR was efficiently dephosphorylated by the full-length form of SHP-2 but not by its SH2 domain-truncated form. Together, the data indicate that PZR serves not only as a specific anchor protein of SHP-2 on the plasma membrane but also as a physiological substrate of the enzyme. The coexisting binding and dephosphorylation of PZR by SHP-2 may function to terminate signal transduction initiated by PZR and SHP-2 and to set a threshold for the signal transduction to be initiated.

Blotting, Western↗
PubMed2002

Glucose regulates insulin mitogenic effect by modulating SHP-2 activation and localization in JAr cells.

The glucose effect on cell growth has been investigated in the JAr human choriocarcinoma cells. When JAr cells were cultured in the presence of 6 mm glucose (LG), proliferation and thymidine incorporation were induced by serum, epidermal growth factor, and insulin-like growth factor 1 but not by insulin. In contrast, at 25 mm glucose (HG), proliferation and thymidine incorporation were stimulated by insulin, serum, epidermal growth factor, and insulin-like growth factor 1 to a comparable extent, whereas basal levels were 25% lower than those in LG. HG culturing also enhanced insulin-stimulated insulin receptor and insulin receptor substrate 1 (IRS1) tyrosine phosphorylations while decreasing basal phosphorylations. These actions of glucose were accompanied by an increase in cellular tyrosine phosphatase activity. The activity of SHP-2 in HG-treated JAr cells was 400% of that measured in LG-treated cells. SHP-2 co-precipitation with IRS1 was also increased in HG-treated cells. SHP-2 was mainly cytosolic in LG-treated cells. However, HG culturing largely redistributed SHP-2 to the internal membrane compartment, where tyrosine-phosphorylated IRS1 predominantly localizes. Further exposure to insulin rescued SHP-2 cytosolic localization, thereby preventing its interaction with IRS1. Antisense inhibition of SHP-2 reverted the effect of HG on basal and insulin-stimulated insulin receptor and IRS1 phosphorylation as well as that on thymidine incorporation. Thus, in JAr cells, glucose modulates insulin mitogenic action by modulating SHP-2 activity and intracellular localization.

3T3 Cells↗
PubMed2002

SHP-2 is a dual-specificity phosphatase involved in Stat1 dephosphorylation at both tyrosine and serine residues in nuclei.

Signal transducer and activator of transcription (STAT) proteins are both tyrosine- and serine-phosphorylated, mediating signal transduction and gene regulation. Following gene regulation, STAT activity in the nucleus is then terminated by a nuclear protein phosphatase(s), which remains unidentified. Using novel antibody arrays to screen the Stat1-specific protein phosphatase(s), we identified a SHP-2-Stat1 interaction in the A431 cell nucleus. SHP-2 and Stat1 nuclear localization and their association in response to either epidermal growth factor or interferon-gamma (IFNgamma) were confirmed by immunofluorescent staining and affinity precipitation assays. The SHP-2 C-terminal region containing protein-tyrosine phosphatase activity interacted with the C-terminal SH2 transcriptional activation domain of Stat1. In SHP-2-/- mouse fibroblast cells, Stat1 phosphorylation at both the tyrosine residue Tyr(701) and the serine residue Ser(727) by IFNgamma was enhanced and prolonged. Consistently, purified GST-SHP-2 dephosphorylated Stat1 at both tyrosine and serine residues when immunoprecipitated phospho-Stat1 or a peptide corresponding to the sequence surrounding Tyr(P)(701) or Ser(P)(727) of Stat1 was used as the substrate. Overexpression of SHP-2 in 293T cells inhibited IFNgamma-dependent Stat1 phosphorylation and suppressed Stat1-dependent induction of luciferase activity. Our findings demonstrate that SHP-2 is a dual-specificity protein phosphatase involved in Stat1 dephosphorylation at both tyrosine and serine residues and plays an important role in modulating STAT function in gene regulation.

Active Transport, Cell Nucleus↗
PubMed2003

Resistance of SHP-null mice to bile acid-induced liver damage.

The orphan nuclear hormone receptor SHP (gene designation NROB2) is an important component of a negative regulatory cascade by which high levels of bile acids repress bile acid biosynthesis. Short term studies in SHP null animals confirm this function and also reveal the existence of additional pathways for bile acid negative feedback regulation. We have used long term dietary treatments to test the role of SHP in response to chronic elevation of bile acids, cholesterol, or both. In contrast to the increased sensitivity predicted from the loss of negative feedback regulation, the SHP null mice were relatively resistant to the hepatotoxicity associated with a diet containing 0.5% cholic acid and the much more severe effects of a diet containing both 0.5% cholic acid and 2% cholesterol. This was associated with decreased hepatic accumulation of cholesterol and triglycerides in the SHP null mice. There were also alterations in the expression of a number of genes involved in cholesterol and bile acid homeostasis, notably cholesterol 12alpha-hydroxylase (CYP8B1), which was strongly reexpressed in the SHP null mice, but not the wild type mice fed either bile acid containing diet. This contrasts with the strong repression of CYP8B1 observed with short term bile acid feeding, as well as the effects of long term feeding on other bile acid biosynthetic enzymes such as cholesterol 7alpha-hydroxylase (CYP7A1). CYP8B1 expression could contribute to the decreased toxicity of the chronic bile acid treatment by increasing the hydrophilicity of the bile acid pool. These results identify an unexpected role for SHP in hepatotoxicity and suggest new approaches to modulating effects of chronically elevated bile acids in cholestasis.

Animals↗
PubMed2007

PU.1 activates transcription of SHP-1 gene in hematopoietic cells.

Protein-tyrosine phosphatase SHP-1 is the key negative regulator of numerous signaling pathways. SHP-1 is expressed in the hematopietic and epithelial cells as two structurally similar mRNA transcripts controlled by two different promoters designated P2 and P1, respectively. Whereas the transcriptional regulation of the SHP-1 gene P1 promoter has been partially elucidated, the structure and functional control of the P2 promoter remain unknown despite the critical role played by SHP-1 in the normal and malignant lymphoid and other hematopoetic cells. Using luciferase reporter assays with the set of constructs that contained a gradually truncated intron 1 of the SHP-1 gene, we identified the minimal (<120 bp) fragment that is able to fully activate expression of the reporter gene. Furthermore, we found that PU.1 (a member of the Ets transcription factor family that plays a crucial role in differentiation and function of the lymphoid and myeloid cells) binds to the identified P2 promoter both in vitro and in vivo. PU.1 also activates the promoter in the sequence specific manner and is critical for its expression as evidenced by the profound supression of the SHP-1 gene transcription upon the siRNA-mediated depletion of PU.1. These findings provide an insight into the structure of the hematopoietic cell-specific P2 promoter of the SHP-1 gene and identify PU.1 as the transcriptional activator of the P2 promoter.

Blood Cells↗
PubMed2007

SHP-2 regulates cell growth by controlling the mTOR/S6 kinase 1 pathway.

Cell growth (accumulation in cell mass) ensues through the promotion of macromolecular biosynthesis. S 6 ribosomal kinase 1 (S6K1), which is activated by the mammalian target of rapamycin, is critical for cell growth. The early events that control S6K1 signaling remain unclear. Here we show that SHP-2 suppresses S6K1 activity under conditions of growth factor deprivation. We show that under conditions of growth factor deprivation, S6K1 activity was increased in fibroblasts lacking functional SHP-2 and in cells where knock down of SHP-2 expression was established by small interference RNA. Consistent with these findings, fibroblasts lacking functional SHP-2 exhibited increased cell size as compared with wild type cells. Growth factor deprivation reduces cellular energy, and the energy-sensing 5'-AMP-activated protein kinase (AMPK) negatively regulates S6K1. We found that SHP-2 promoted AMPK activity under conditions of growth factor deprivation (low energy), suggesting that SHP-2 negatively regulates S6K1 via an AMPK-dependent pathway. These results implicate SHP-2 as an early mediator in the S6K1 signaling pathway to limit cell growth in low energy states.

Adenylate Kinase↗
PubMed2003

SHP-1 negatively regulates neuronal survival by functioning as a TrkA phosphatase.

Nerve growth factor (NGF) mediates the survival and differentiation of neurons by stimulating the tyrosine kinase activity of the TrkA/NGF receptor. Here, we identify SHP-1 as a phosphotyrosine phosphatase that negatively regulates TrkA. SHP-1 formed complexes with TrkA at Y490, and dephosphorylated it at Y674/675. Expression of SHP-1 in sympathetic neurons induced apoptosis and TrkA dephosphorylation. Conversely, inhibition of endogenous SHP-1 with a dominant-inhibitory mutant stimulated basal tyrosine phosphorylation of TrkA, thereby promoting NGF-independent survival and causing sustained and elevated TrkA activation in the presence of NGF. Mice lacking SHP-1 had increased numbers of sympathetic neurons during the period of naturally occurring neuronal cell death, and when cultured, these neurons survived better than wild-type neurons in the absence of NGF. These data indicate that SHP-1 can function as a TrkA phosphatase, controlling both the basal and NGF-regulated level of TrkA activity in neurons, and suggest that SHP-1 regulates neuron number during the developmental cell death period by directly regulating TrkA activity.

Animals↗
PubMed1997

Downregulated expression of SHP-1 in Burkitt lymphomas and germinal center B lymphocytes.

We wish to identify developmental changes in germinal center B cells that may contribute to their rapid growth. SHP-1 is an SH2 domain-containing phosphotyrosine phosphatase that negatively regulates activation of B cells and other cells of hematopoietic lineages. We have found that in all 13 EBV-negative and 11 EBV-positive Burkitt lymphomas with a nonlymphoblastoid phenotype, the mean concentration of SHP-1 was reduced to 5% of that of normal B and T cells. The possibility that this diminished expression of SHP-1 was related to the germinal center phenotype of Burkitt lymphomas was supported by the low to absent immunofluorescent staining for SHP-1 in germinal centers, and by the inverse relationship between the concentration of SHP-1 and the expression of the germinal center marker CD38 on purified tonsillar B cells. In CD38-high B cells, SHP-1 concentration was 20% of that of mantle zone B cells from the same donor. This reduction in SHP-1 is comparable to that of cells from motheaten viable mev/mev mice in which there is dysregulated, spontaneous signaling by cytokine and antigen receptors. Therefore, germinal center B cells may have a developmentally regulated, low threshold for cellular activation.

B-Lymphocytes↗
PubMed2001

Neuronal nitric oxide synthase: a substrate for SHP-1 involved in sst2 somatostatin receptor growth inhibitory signaling.

Somatostatin receptor sst2 is an inhibitory G protein-coupled receptor, which inhibits normal and tumor cell growth by a mechanism involving the tyrosine phosphatase SHP-1. We reported previously that SHP-1 associates transiently with and is activated by sst2 and is a critical component for sst2 growth inhibitory signaling. Here, we demonstrate that in Chinese hamster ovary cells expressing sst2, SHP-1 is associated at the basal level with the neuronal nitric oxide synthase (nNOS). Following sst2 activation by the somatostatin analog RC-160, SHP-1 rapidly recruits nNOS tyrosine dephosphorylates and activates it. The resulting NO activates guanylate cyclase and inhibits cell proliferation. Coexpression of a catalytically inactive SHP-1 mutant with sst2 blocks RC-160-induced nNOS dephosphorylation and activation, as well as guanylate cyclase activation. In mouse pancreatic acini, RC-160 treatment reduces nNOS tyrosine phosphorylation accompanied by an increase of its activity. By opposition, in acini from viable motheaten (mev/mev) mice, which express a markedly inactive SHP-1, RC-160 has no effect on nNOS activity. Finally, expression of a dominant-negative form of nNOS prevents both RC-160-induced p27 up-regulation and cell proliferation inhibition. We therefore identified nNOS as a novel SHP-1 substrate critical for sst2-induced cell-growth arrest.

Animals↗
PubMed1996

A novel membrane glycoprotein, SHPS-1, that binds the SH2-domain-containing protein tyrosine phosphatase SHP-2 in response to mitogens and cell adhesion.

Protein tyrosine phosphatases (PTPases), such as SHP-1 and SHP-2, that contain Src homology 2 (SH2) domains play important roles in growth factor and cytokine signal transduction pathways. A protein of approximately 115 to 120 kDa that interacts with SHP-1 and SHP-2 was purified from v-src-transformed rat fibroblasts (SR-3Y1 cells), and the corresponding cDNA was cloned. The predicted amino acid sequence of the encoded protein, termed SHPS-1 (SHP substrate 1), suggests that it 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 SH2-domain binding sites, in its cytoplasmic region. Various mitogens, including serum, insulin, and lysophosphatidic acid, or cell adhesion induced tyrosine phosphorylation of SHPS-1 and its subsequent association with SHP-2 in cultured cells. Thus, SHPS-1 may be a direct substrate for both tyrosine kinases, such as the insulin receptor kinase or Src, and a specific docking protein for SH2-domain-containing PTPases. In addition, we suggest that SHPS-1 may be a potential substrate for SHP-2 and may function in both growth factor- and cell adhesion-induced cell signaling.

Amino Acid Sequence↗
PubMed2002

Tumor necrosis factor-alpha inhibits growth factor-mediated cell proliferation through SHP-1 activation in endothelial cells.

Src homology 2-containing protein-tyrosine phosphatase 1 (SHP-1) is known to regulate signal transduction through the dephosphorylation of tyrosine kinases. In this study, we addressed the role of SHP-1 under tumor necrosis factor-alpha (TNF-alpha) stimulation in endothelial cells. The addition of recombinant vascular endothelial growth factor (50 ng/mL) or epidermal growth factor (50 ng/mL) significantly increased thymidine incorporation and c-fos promoter activity, whereas TNF-alpha (5 ng/mL) attenuated these effects in human or bovine aortic endothelial cells. In bovine aortic endothelial cells, we confirmed endogenous SHP-1 expression and that TNF-alpha activated SHP-1. Importantly, overexpression of dominant-negative SHP-1 attenuated the effect of TNF-alpha on thymidine incorporation and c-fos promoter activity. In addition, TNF-alpha attenuated vascular endothelial growth factor- and epidermal growth factor-induced extracellular signal-regulated kinase phosphorylation, whereas overexpression of dominant-negative SHP-1 prevented this inhibitory effect of TNF-alpha. Taken together, our results suggested that TNF-alpha inhibited growth factor-mediated cell proliferation through SHP-1 activation.

Animals↗
PubMed2003

The effect of phosphatases SHP-1 and SHIP-1 on signaling by the ITIM- and ITAM-containing Fcgamma receptors FcgammaRIIB and FcgammaRIIA.

Inositol and tyrosine phosphatases have been implicated in inhibitory signaling by an Fc receptor for immunoglobulin G, FcgammaRIIB, in B cells, mast cells, and monocytes. Here, we propose a role for the Src homology 2 (SH2)-containing tyrosine phosphatase-1 (SHP-1) in FcgammaRIIB-mediated inhibition of FcgammaR signaling. Coexpression of SHP-1 enhances FcgammaRIIB-mediated inhibition of FcgammaRIIA phagocytosis in COS-1 cells. SHP-1 also enhances the reduction in FcgammaRIIA tyrosine phosphorylation that accompanies this inhibition. Significantly, tyrosine phosphorylation of Syk kinase is substantially inhibited by SHP-1. Furthermore, the activation of SHP-1 tyrosine phosphorylation is observed following stimulation of FcgammaRII in COS-1 cells and in human monocytes. The SH2 domain containing inositol phosphatase (SHIP), SHIP-1 also enhances FcgammaRIIB-mediated inhibition of FcgammaRIIA, indicating that FcgammaRIIB can use more than one pathway for its inhibitory action. In addition, SHP-1 and SHIP-1 can inhibit FcgammaRIIA phagocytosis and signal transduction in the absence of FcgammaRIIB. The data support emerging evidence that SH2-containing phosphatases, such as SHP-1 and SHIP-1, can modulate signaling by "activating" receptors.

Amino Acid Motifs↗