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Christina Anne Mitchell - One of the best experts on this subject based on the ideXlab platform.

  • regulation of ptdins 3 4 5 p3 akt signalling by inositol polyphosphate 5 phosphatases
    Biochemical Society Transactions, 2016
    Co-Authors: Matthew J Eramo, Christina Anne Mitchell
    Abstract:

    The phosphoinositide 3-kinase (PI3K) generated lipid signals, PtdIns(3,4,5) P 3 and PtdIns(3,4) P 2, are both required for the maximal activation of the serine/threonine kinase proto-oncogene Akt. The inositol polyphosphate 5-Phosphatases (5-Phosphatases) hydrolyse the 5-position phosphate from the inositol head group of PtdIns(3,4,5) P 3 to yield PtdIns(3,4) P 2. Extensive work has revealed several 5-Phosphatases inhibit PI3K-driven Akt signalling, by decreasing PtdIns(3,4,5) P 3 despite increasing cellular levels of PtdIns(3,4) P 2. The roles that 5-Phosphatases play in suppressing cell proliferation and transformation are slow to emerge; however, the 5-Phosphatase PIPP [proline-rich inositol polyphosphate 5-Phosphatase; inositol polyphosphate 5-Phosphatase ( INPP5J )] has recently been identified as a putative tumour suppressor in melanoma and breast cancer and SHIP1 [SH2 (Src homology 2)-containing inositol phosphatase 1] inhibits haematopoietic cell proliferation. INPP5E regulates cilia stability and INPP5E mutations have been implicated ciliopathy syndromes. This review will examine 5-Phosphatase regulation of PI3K/Akt signalling, focussing on the role PtdIns(3,4,5) P 3 5-Phosphatases play in developmental diseases and cancer. * 3AC, : 3-a-aminocholestane; 5-Phosphatases, : inositol polyphosphate 5-Phosphatases; AURKA, : aurora kinase A; BJAB, : human B-cell lymphoma cell line; BMMC, : bone marrow-derived mast cells; CHO, : Chinese hamster ovary; EGF, : epidermal growth factor; ENU, : N -ethyl- N -nitrosourea; ER, : estrogen receptor; FoxO, : forkhead box, class O; GLUT4, : glucose transporter type 4; Gpr161, : G-protein-coupled receptor 161; HEK, : human embryonic kidney; IGF-1, : insulin-like growth factor-1; IL-3, : interleukin-3; LPS, : lipopolysaccharide; MEF, : mouse embryonic fibroblast; MM, : multiple myeloma; mTORC, : mammalian target of rapamycin complex; NFAT, : nuclear factor of activated T cells; OCRL, : oculocerebrorenal syndrome of Lowe; Pak1, : P21-activated kinase 1; PDK1, : phosphoinositide-dependent kinase 1; PH, : pleckstrin homology; 1PIE, : (2-phenyl-benzo[ h ]quinolin-4-yl)-[2]piperidyl-methanol hydrochloride; 2PIQ, : 1-[(chlorophenyl)methyl]-2-methyl-5-(methylthio)-1H-indole-3-ethanamine hydrochloride; 6PTQ, : (2-adamantan-1-yl-6,8-dichloro-quinolin-4-yl)-pyridin-2-yl-methanol hydrochloride; PI3K, : phosphoinositide 3-kinase; PIPP, : proline-rich inositol polyphosphate 5-Phosphatase; PRAS40, : proline-rich Akt substrate of 40 kDa; PTEN, : phosphatase and tensin homologue deleted on chromosome 10; PyMT, : polyoma middle T; Rheb, : Ras homologue enriched in brain; RhoGAP, : Rho GTP-ase activating protein; SAG, : smoothened agonist; Shh, : sonic hedgehog; SHIP, : SH2-containing inositol phosphatase; SKICH, : SKIP carboxy homology; SKIP, : skeletal muscle- and kidney-enriched inositol phosphatase; TNFα, : tumour necrosis factor α; TSC, : tuberous sclerosis; TULP3, : Tubby-like protein 3

  • inpp5e interacts with aurka linking phosphoinositide signaling to primary cilium stability
    Journal of Cell Science, 2015
    Co-Authors: Olga V Plotnikova, Christina Anne Mitchell, Jennifer M Dyson, Sandra Hakim, Sarah E Conduit, Seongjin Seo, Denny L Cottle, Ian M Smyth
    Abstract:

    Mutations in inositol polyphosphate 5-Phosphatase E (INPP5E) cause the ciliopathies known as Joubert and MORM syndromes; however, the role of INPP5E in ciliary biology is not well understood. Here, we describe an interaction between INPP5E and AURKA, a centrosomal kinase that regulates mitosis and ciliary disassembly, and we show that this interaction is important for the stability of primary cilia. Furthermore, AURKA phosphorylates INPP5E and thereby increases its 5-Phosphatase activity, which in turn promotes transcriptional downregulation of AURKA, partly through an AKT-dependent mechanism. These findings establish the first direct link between AURKA and phosphoinositide signaling and suggest that the function of INPP5E in cilia is at least partly mediated by its interactions with AURKA.

  • a mutation in synaptojanin 2 causes progressive hearing loss in the enu mutagenised mouse strain mozart
    PLOS ONE, 2011
    Co-Authors: Shehnaaz S M Manji, Christina Anne Mitchell, Lisa M Ooms, Louise L Williams, Kerry A Miller, Melanie Bahlo, Hanshenrik M Dahl
    Abstract:

    Background Hearing impairment is the most common sensory impairment in humans, affecting 1:1,000 births. We have identified an ENU generated mouse mutant, Mozart, with recessively inherited, non-syndromic progressive hearing loss caused by a mutation in the synaptojanin 2 (Synj2), a central regulatory enzyme in the phosphoinositide-signaling cascade. Methodology/Principal Findings The hearing loss in Mozart is caused by a p.Asn538Lys mutation in the catalytic domain of the inositol polyphosphate 5-Phosphatase synaptojanin 2. Within the cochlea, Synj2 mRNA expression was detected in the inner and outer hair cells but not in the spiral ganglion. Synj2N538K mutant protein showed loss of lipid phosphatase activity, and was unable to degrade phosphoinositide signaling molecules. Mutant Mozart mice (Synj2N538K/N538K) exhibited progressive hearing loss and showed signs of hair cell degeneration as early as two weeks of age, with fusion of stereocilia followed by complete loss of hair bundles and ultimately loss of hair cells. No changes in vestibular or neurological function, or other clinical or behavioral manifestations were apparent. Conclusions/Significance Phosphoinositides are membrane associated signaling molecules that regulate many cellular processes including cell death, proliferation, actin polymerization and ion channel activity. These results reveal Synj2 as a critical regulator of hair cell survival that is essential for hair cell maintenance and hearing function.

  • the inositol polyphosphate 5 phosphatase pipp is a novel regulator of phosphoinositide 3 kinase dependent neurite elongation
    Molecular Biology of the Cell, 2005
    Co-Authors: Lisa M Ooms, Megan Victoria Astle, Clare G Fedele, Meredith J. Layton, Harshal Hanumant Nandurkar, Ivan Ivetac, V Cheung, Richard B Pearson, Ariel Forrai, Christina Anne Mitchell
    Abstract:

    The spatial activation of phosphoinositide 3-kinase (PI3-kinase) signaling at the axon growth cone generates phosphatidylinositol 3,4,5 trisphosphate (PtdIns(3,4,5)P3), which localizes and facilitates Akt activation and stimulates GSK-3beta inactivation, promoting microtubule polymerization and axon elongation. However, the molecular mechanisms that govern the spatial down-regulation of PtdIns(3,4,5)P3 signaling at the growth cone remain undetermined. The inositol polyphosphate 5-Phosphatases (5-Phosphatase) hydrolyze the 5-position phosphate from phosphatidylinositol 4,5 bisphosphate (PtdIns(4,5)P2) and/or PtdIns(3,4,5)P3. We demonstrate here that PIPP, an uncharacterized 5-Phosphatase, hydrolyzes PtdIns(3,4,5)P3 forming PtdIns(3,4)P2, decreasing Ser473-Akt phosphorylation. PIPP is expressed in PC12 cells, localizing to the plasma membrane of undifferentiated cells and the neurite shaft and growth cone of NGF-differentiated neurites. Overexpression of wild-type, but not catalytically inactive PIPP, in PC12 cells inhibited neurite elongation. Targeted depletion of PIPP using RNA interference (RNAi) resulted in enhanced neurite differentiation, associated with neurite hyperelongation. Inhibition of PI3-kinase activity prevented neurite hyperelongation in PIPP-deficient cells. PIPP targeted-depletion resulted in increased phospho-Ser473-Akt and phospho-Ser9-GSK-3beta, specifically at the neurite growth cone, and accumulation of PtdIns(3,4,5)P3 at this site, associated with enhanced microtubule polymerization in the neurite shaft. PIPP therefore inhibits PI3-kinase-dependent neurite elongation in PC12 cells, via regulation of the spatial distribution of phospho-Ser473-Akt and phospho-Ser9-GSK-3beta signaling.

  • the inositol polyphosphate 5 phosphatase pipp is a novel regulator of phosphoinositide 3 kinase dependent neurite elongation
    Molecular Biology of the Cell, 2005
    Co-Authors: Lisa M Ooms, Megan Victoria Astle, Clare G Fedele, Meredith J. Layton, Harshal Hanumant Nandurkar, Ivan Ivetac, V Cheung, Richard B Pearson, Ariel Forrai, Christina Anne Mitchell
    Abstract:

    The spatial activation of phosphoinositide 3-kinase (PI3-kinase) signaling at the axon growth cone generates phosphatidylinositol 3,4,5 trisphosphate (PtdIns(3,4,5)P3), which localizes and facilita...

Philip W. Majerus - One of the best experts on this subject based on the ideXlab platform.

  • The inositol polyphosphate 5-Phosphatase Ocrl associates with endosomes that are partially coated with clathrin
    Proceedings of the National Academy of Sciences, 2004
    Co-Authors: Alexander Ungewickell, Michael Ward, Ernst J. Ungewickell, Philip W. Majerus
    Abstract:

    The subcellular localization of Ocrl, the inositol polyphosphate 5-Phosphatase that is mutated in Lowe syndrome, was investigated by fluorescence microscopy. Ocrl was localized to endosomes and Golgi membranes along with clathrin, giantin, the mannose 6-phosphate receptor, transferrin, and the early endosomal antigen 1 endosomal marker in fixed cells. The endosomal localization of Ocrl was confirmed by live-cell time-lapse microscopy in which we monitored the dynamics of Ocrl on endosomes. GST binding assays show that Ocrl interacts with the clathrin terminal domain and the clathrin adaptor protein AP-2. Our findings suggest a role for Ocrl in endosomal receptor trafficking and sorting.

  • phosphoinositide specific inositol polyphosphate 5 phosphatase iv inhibits akt protein kinase b phosphorylation and leads to apoptotic cell death
    Journal of Biological Chemistry, 2002
    Co-Authors: Li Cao, Philip W. Majerus
    Abstract:

    Abstract Phosphoinositide-specific inositol polyphosphate 5- phosphatase IV has the affinity for PI(3,4,5)P3 (K m = 0.65 μM) that is approximately 10-fold greater than the other inositol polyphosphate 5-Phosphatases, which use this substrate including SHIP, OCRL, and 5ptase II, suggesting that it may be important in controlling intracellular levels of this metabolite. We created cell lines stably expressing the enzyme to study its effect on cell function. We found that overexpression of 5ptase IV in 293 cells caused the rapid depletion of both PI(4,5)P2 and PI(3,4,5)P3 in cells with corresponding increases in the products, PI(4)P and PI(3,4)P2, changing the balance of two phosphoinositol products of phosphoinositide 3-kinase, PI(3,4)P2 and PI(3,4,5)P3, in the cell. One of the targets of these phosphoinositides is the serine/threonine kinase Akt, which plays an important role in the control of apoptosis. We were able to address the relative roles of PI(3,4)P2 and PI(3,4,5)P3 in the activation of Akt by selective depletion of these phosphoinositides in cells stably transfected with 5ptase IV and inositol polyphosphate 4-phosphatase (4ptase I). In cells transfected with 4ptase I, the level of PI(3,4)P2 was reduced, and PI(3,4,5)P3 was increased. Expression of the two enzymes had the opposite effect on the phosphorylation of Akt in response to stimulation with growth factors or heat shock. Akt phosphorylation was inhibited in cells expressing 5ptase IV but increased in 4ptase I cells and correlated with the intracellular level of PI(3,4,5)P3 and not that of PI(3,4)P2. The inhibition of Akt phosphorylation in cells expressing 5ptase IV makes them highly susceptible to FAS-induced apoptosis, whereas overexpressing of the 4ptase I protects cells from apoptosis. Our results place 5ptase IV as a relevant biological regulator of PI3K/Akt pathway in cells.

  • The isolation and characterization of a cDNA encoding phospholipid-specific inositol polyphosphate 5-Phosphatase.
    Journal of Biological Chemistry, 2000
    Co-Authors: Monita P. Wilson, Philip W. Majerus
    Abstract:

    Abstract We report the cDNA cloning and characterization of a novel human inositol polyphosphate 5-Phosphatase (5-Phosphatase) that has substrate specificity unlike previously described members of this large gene family. All previously described members hydrolyze water soluble inositol phosphates. This enzyme hydrolyzes only lipid substrates, phosphatidylinositol 3,4,5-trisphosphate and phosphatidylinositol 4,5-bisphosphate. The cDNA isolated comprises 3110 base pairs and predicts a protein product of 644 amino acids and M r = 70,023. We designate this 5-Phosphatase as type IV. It is a highly basic protein (pI = 8.8) and has the greatest affinity toward phosphatidylinositol 3,4,5-trisphosphate of known 5-Phosphatases. TheK m is 0.65 μm, 1/10 that of SHIP (5.95 μm), another 5-Phosphatase that hydrolyzes phosphatidylinositol 3,4,5-trisphosphate. The activity of 5-Phosphatase type IV is sensitive to the presence of detergents in the in vitro assay. Thus the enzyme hydrolyzes lipid substrates in the absence of detergents or in the presence of n-octyl β-glucopyranoside or Triton X-100, but not in the presence of cetyltriethylammonium bromide, the detergent that has been used in other studies of the hydrolysis of phosphatidylinositol 4,5-bisphosphate. Remarkably SHIP, a 5-Phosphatase previously characterized as hydrolyzing only substrates with d-3 phosphates, also readily hydrolyzed phosphatidylinositol 4,5-bisphosphate in the presence of n-octyl β-glucopyranoside but not cetyltriethylammonium bromide. We used antibodies prepared against a peptide predicted by the cDNA to identify the 5-Phosphatase type IV enzyme in human tissues and find that it is highly expressed in the brain as determined by Western blotting. We also performed Western blotting of mouse tissues and found high levels of expression in the brain, testes, and heart with lower levels of expression in other tissues. mRNA was detected in many tissues and cell lines as determined by Northern blotting.

  • Cell lines from kidney proximal tubules of a patient with Lowe syndrome lack OCRL inositol polyphosphate 5-Phosphatase and accumulate phosphatidylinositol 4,5-bisphosphate.
    Journal of Biological Chemistry, 1998
    Co-Authors: Xiaoling Zhang, Patricia A. Hartz, Elizabeth T. Philip, Lorraine C. Racusen, Philip W. Majerus
    Abstract:

    The protein product of the gene that when mutated is responsible for Lowe syndrome, or oculocerebrorenal syndrome (OCRL), is an inositol polyphosphate 5-Phosphatase. It has a marked preference for phosphatidylinositol 4,5-bisphosphate although it hydrolyzes all four of the known inositol polyphosphate 5-Phosphatase substrates: inositol 1,4,5-trisphosphate, inositol 1,3,4,5-tetrakisphosphate, phosphatidylinositol 4,5-bisphosphate, and phosphatidylinositol 3,4,5-trisphosphate. The enzyme activity of this protein is determined by a region of 672 out of a total of 970 amino acids that is homologous to inositol polyphosphate 5-Phosphatase II. Cell lines from kidney proximal tubules of a patient with Lowe syndrome and a normal individual were used to study the function of OCRL. The cells from the Lowe syndrome patient lack OCRL protein. OCRL is the major phosphatidylinositol 4,5-bisphosphate 5-Phosphatase in these cells. As a result, these cells accumulate phosphatidylinositol 4,5-bisphosphate even though at least four other inositol polyphosphate 5-Phosphatase isozymes are present in these cells. OCRL is associated with lysosomal membranes in control proximal tubule cell lines suggesting that OCRL may function in lysosomal membrane trafficking by regulating the specific pool of phosphatidylinositol 4,5-bisphosphate that is associated with lysosomes.

  • Multiple forms of an inositol polyphosphate 5-Phosphatase form signaling complexes with Shc and Grb2
    Current Biology, 1996
    Co-Authors: W M Kavanaugh, Philip W. Majerus, David Pot, S.m. Chin, M. Deuter-reinhard, Ann B. Jefferson, F A Norris, F.r. Masiarz, Lawrence S. Cousens, Lewis T. Williams
    Abstract:

    Abstract Background: Shc and Grb2 form a complex in cells in response to growth factor stimulation and link tyrosine kinases to Ras during the resulting signaling process. Shc and Grb2 each contain domains that mediate interactions with other unidentified intracellular proteins. For example, the Shc PTB domain binds to 130 kDa and 145 kDa tyrosine-phosphorylated proteins in response to stimulation of cells by growth factors, cytokines and crosslinking of antigen receptors. The Grb2 SH3 domains bind to an unidentified 116 kDa protein in T cells. We have identified three proteins, of 110 kDa, 130 kDa and 145 kDa, as a new family of molecules encoded by the same gene. In vivo studies show that these proteins form signal transduction complexes with Shc and with Grb2. Results The 130 kDa and 145 kDa tyrosine-phosphorylated proteins that associate with the Shc PTB domain were purified by conventional chromatographic methods. Partial peptide and cDNA sequences corresponding to these proteins, termed SIP-145 and SIP-130 (SIP for signaling inositol polyphosphate 5-Phosphatase), identified them as SH2 domain-containing products of a single gene and as members of the inositol polyphosphate 5-Phosphatase family. The SIP-130 and SIP-145 proteins and inositol polyphosphate 5-Phosphatase activity associated with Shc in vivo in response to B-cell activation. By using an independent approach, expression cloning, we found that the Grb2 SH3 domains bind specifically to SIP-110, a 110 kDa splice variant of SIP-145 and SIP-130, which lacks the SH2 domain. The SIP proteins hydrolyzed phosphatidylinositol (3,4,5)-trisphosphate (PtdIns (3,4,5)-P 3 ) and Ins (1,3,4,5)-P 4 , but not PtdIns (4,5)-P 2 or Ins (1,4,5)-P 3 . Conclusion These findings strongly implicate the inositol polyphosphate 5-Phosphatases in Shc- and Grb2-mediated signal transduction. Furthermore, SIP-110, SIP-130 and SIP-145 prefer 3-phosphorylated substrates, suggesting a link to the phosphatidylinositol 3-kinase signaling pathway.

Lisa M Ooms - One of the best experts on this subject based on the ideXlab platform.

  • The Inositol Polyphosphate 5-Phosphatase PIPP Regulates AKT1-Dependent Breast Cancer Growth and Metastasis
    Cancer Cell, 2015
    Co-Authors: Lisa M Ooms, Rajendra Gurung, Lauren C. Binge, Elizabeth M. Davies, Parvin Rahman, James R.w. Conway, Daniel T. Ferguson, Antonella Papa, Clare G Fedele, Jessica L. Vieusseux
    Abstract:

    Metastasis is the major cause of breast cancer mortality. Phosphoinositide 3-kinase (PI3K) generated PtdIns(3,4,5)P3 activates AKT, which promotes breast cancer cell proliferation and regulates migration. To date, none of the inositol polyphosphate 5-Phosphatases that inhibit PI3K/AKT signaling have been reported as tumor suppressors in breast cancer. Here, we show depletion of the inositol polyphosphate 5-Phosphatase PIPP (INPP5J) increases breast cancer cell transformation, but reduces cell migration and invasion. Pipp ablation accelerates oncogene-driven breast cancer tumor growth in vivo, but paradoxically reduces metastasis by regulating AKT1-dependent tumor cell migration. PIPP mRNA expression is reduced in human ER-negative breast cancers associated with reduced long-term outcome. Collectively, our findings identify PIPP as a suppressor of oncogenic PI3K/AKT signaling in breast cancer.

  • a mutation in synaptojanin 2 causes progressive hearing loss in the enu mutagenised mouse strain mozart
    PLOS ONE, 2011
    Co-Authors: Shehnaaz S M Manji, Christina Anne Mitchell, Lisa M Ooms, Louise L Williams, Kerry A Miller, Melanie Bahlo, Hanshenrik M Dahl
    Abstract:

    Background Hearing impairment is the most common sensory impairment in humans, affecting 1:1,000 births. We have identified an ENU generated mouse mutant, Mozart, with recessively inherited, non-syndromic progressive hearing loss caused by a mutation in the synaptojanin 2 (Synj2), a central regulatory enzyme in the phosphoinositide-signaling cascade. Methodology/Principal Findings The hearing loss in Mozart is caused by a p.Asn538Lys mutation in the catalytic domain of the inositol polyphosphate 5-Phosphatase synaptojanin 2. Within the cochlea, Synj2 mRNA expression was detected in the inner and outer hair cells but not in the spiral ganglion. Synj2N538K mutant protein showed loss of lipid phosphatase activity, and was unable to degrade phosphoinositide signaling molecules. Mutant Mozart mice (Synj2N538K/N538K) exhibited progressive hearing loss and showed signs of hair cell degeneration as early as two weeks of age, with fusion of stereocilia followed by complete loss of hair bundles and ultimately loss of hair cells. No changes in vestibular or neurological function, or other clinical or behavioral manifestations were apparent. Conclusions/Significance Phosphoinositides are membrane associated signaling molecules that regulate many cellular processes including cell death, proliferation, actin polymerization and ion channel activity. These results reveal Synj2 as a critical regulator of hair cell survival that is essential for hair cell maintenance and hearing function.

  • the inositol polyphosphate 5 phosphatase pipp is a novel regulator of phosphoinositide 3 kinase dependent neurite elongation
    Molecular Biology of the Cell, 2005
    Co-Authors: Lisa M Ooms, Megan Victoria Astle, Clare G Fedele, Meredith J. Layton, Harshal Hanumant Nandurkar, Ivan Ivetac, V Cheung, Richard B Pearson, Ariel Forrai, Christina Anne Mitchell
    Abstract:

    The spatial activation of phosphoinositide 3-kinase (PI3-kinase) signaling at the axon growth cone generates phosphatidylinositol 3,4,5 trisphosphate (PtdIns(3,4,5)P3), which localizes and facilitates Akt activation and stimulates GSK-3beta inactivation, promoting microtubule polymerization and axon elongation. However, the molecular mechanisms that govern the spatial down-regulation of PtdIns(3,4,5)P3 signaling at the growth cone remain undetermined. The inositol polyphosphate 5-Phosphatases (5-Phosphatase) hydrolyze the 5-position phosphate from phosphatidylinositol 4,5 bisphosphate (PtdIns(4,5)P2) and/or PtdIns(3,4,5)P3. We demonstrate here that PIPP, an uncharacterized 5-Phosphatase, hydrolyzes PtdIns(3,4,5)P3 forming PtdIns(3,4)P2, decreasing Ser473-Akt phosphorylation. PIPP is expressed in PC12 cells, localizing to the plasma membrane of undifferentiated cells and the neurite shaft and growth cone of NGF-differentiated neurites. Overexpression of wild-type, but not catalytically inactive PIPP, in PC12 cells inhibited neurite elongation. Targeted depletion of PIPP using RNA interference (RNAi) resulted in enhanced neurite differentiation, associated with neurite hyperelongation. Inhibition of PI3-kinase activity prevented neurite hyperelongation in PIPP-deficient cells. PIPP targeted-depletion resulted in increased phospho-Ser473-Akt and phospho-Ser9-GSK-3beta, specifically at the neurite growth cone, and accumulation of PtdIns(3,4,5)P3 at this site, associated with enhanced microtubule polymerization in the neurite shaft. PIPP therefore inhibits PI3-kinase-dependent neurite elongation in PC12 cells, via regulation of the spatial distribution of phospho-Ser473-Akt and phospho-Ser9-GSK-3beta signaling.

  • the inositol polyphosphate 5 phosphatase pipp is a novel regulator of phosphoinositide 3 kinase dependent neurite elongation
    Molecular Biology of the Cell, 2005
    Co-Authors: Lisa M Ooms, Megan Victoria Astle, Clare G Fedele, Meredith J. Layton, Harshal Hanumant Nandurkar, Ivan Ivetac, V Cheung, Richard B Pearson, Ariel Forrai, Christina Anne Mitchell
    Abstract:

    The spatial activation of phosphoinositide 3-kinase (PI3-kinase) signaling at the axon growth cone generates phosphatidylinositol 3,4,5 trisphosphate (PtdIns(3,4,5)P3), which localizes and facilita...

  • the sh2 containing inositol polyphosphate 5 phosphatase ship 2 binds filamin and regulates submembraneous actin
    Journal of Cell Biology, 2001
    Co-Authors: Jennifer M Dyson, Lisa M Ooms, Harshal Hanumant Nandurkar, Cindy J Omalley, Jelena Becanovic, Adam D Munday, Michael C Berndt, Imogen Denise Coghill, Christina Anne Mitchell
    Abstract:

    SHIP-2 is a phosphoinositidylinositol 3,4,5 trisphosphate (PtdIns[3,4,5]P3) 5-Phosphatase that contains an NH2-terminal SH2 domain, a central 5-Phosphatase domain, and a COOH-terminal proline-rich domain. SHIP-2 negatively regulates insulin signaling. In unstimulated cells, SHIP-2 localized in a perinuclear cytosolic distribution and at the leading edge of the cell. Endogenous and recombinant SHIP-2 localized to membrane ruffles, which were mediated by the COOH-terminal proline–rich domain. To identify proteins that bind to the SHIP-2 proline–rich domain, yeast two-hybrid screening was performed, which isolated actin-binding protein filamin C. In addition, both filamin A and B specifically interacted with SHIP-2 in this assay. SHIP-2 coimmunoprecipitated with filamin from COS-7 cells, and association between these species did not change after epidermal growth factor stimulation. SHIP-2 colocalized with filamin at Z-lines and the sarcolemma in striated muscle sections and at membrane ruffles in COS-7 cells, although the membrane ruffling response was reduced in cells overexpressing SHIP-2. SHIP-2 membrane ruffle localization was dependent on filamin binding, as SHIP-2 was expressed exclusively in the cytosol of filamin-deficient cells. Recombinant SHIP-2 regulated PtdIns(3,4,5)P3 levels and submembraneous actin at membrane ruffles after growth factor stimulation, dependent on SHIP-2 catalytic activity. Collectively these studies demonstrate that filamin-dependent SHIP-2 localization critically regulates phosphatidylinositol 3 kinase signaling to the actin cytoskeleton.

Jeffrey V. Ravetch - One of the best experts on this subject based on the ideXlab platform.

  • cutting edge role of the inositol phosphatase ship in b cell receptor induced ca2 oscillatory response
    Journal of Immunology, 1998
    Co-Authors: Hidetaka Okada, Jeffrey V. Ravetch, Mari Kurosaki, Silvia Bolland, Akiko Hashimoto, Yukihito Kabuyama, Masamitsu Iino, Tomohiro Kurosaki
    Abstract:

    Src homology-2 domain-containing inositol polyphosphate 5'-phosphatase (SHIP) is a recently identified protein that has been implicated as an important signaling molecule. Although SHIP has been shown to participate in the FcgammaRIIB-mediated inhibitory signal, the functional role of SHIP in activation responses by immunoreceptor tyrosine-based activation motif-bearing receptors such as B cell receptor (BCR) remains unclear. Indeed, it has been proposed that SHIP serves as a linking molecule for the regulation of the extracellular signal-regulated kinase pathway in BCR signaling, because SHIP associates with Shc. We now report that SHIP-deficient DT40 B cells display enhanced Ca2+ mobilization in response to BCR ligation, whereas extracellular signal-regulated kinase activation is unaffected. This Ca2+ enhancement is due to a sustained intracellular Ca2+ increase or to long-lasting Ca2+ oscillations by loss of SHIP, as revealed by single-cell Ca2+ imaging analysis. These results demonstrate the importance of SHIP in B cell activation by the modulation of Ca2+ mobilization.

  • role of the inositol phosphatase ship in negative regulation of the immune system by the receptor feγriib
    Nature, 1996
    Co-Authors: Jeffrey V. Ravetch, Masao Ono, Silvia Olland, Paul Temps
    Abstract:

    IMMUNE complexes are potent activators of inflammatory cells, triggering effector responses through the crosslinking of Fc receptors (FcRs) such as FcΣRI or FcγRIII (ref. 1). On B cells and mast cells, immune complexes are also negative regulators of activation triggered by antigen and Fc receptors, a consequence of coligation of the B-cell antigen receptor or FcΣRI, respectively, and the inhibitory receptor FcγRIIB. Here we show that inhibitory signalling by FcγRIIB does not require the SH2-domain-containing protein tyrosine phosphatase, SHP-1, in mast cells and results in the recruitment of the SH2-domain-containing inositol polyphosphate 5-Phosphatase, SHIP, to the tyrosine-phosphorylated 13-amino-acid inhibitory motif of FcγRIIB in both B cells and mast cells. SHIP, by hydrolysing the 5-phosphate of phosphatidylinositol(3,4,5)P3 and inositol(l,3,4,5)P4, suggests a mechanism by which FcγRIIB can inhibit calcium influx and downstream responses triggered by immune receptors.

  • role of the inositol phosphatase ship in negative regulation of the immune system by the receptor feγriib
    Nature, 1996
    Co-Authors: Masao Ono, Jeffrey V. Ravetch, Silvia Bolland, Paul Tempst
    Abstract:

    Immune complexes are potent activators of inflammatory cells, triggering effector responses through the crosslinking of Fc receptors (FcRs) such as Fc(epsilon)RI or Fc(gamma)RIII. On B cells and mast cells, immune complexes are also negative regulators of activation triggered by antigen and Fc receptors, a consequence of coligation of the B-cell antigen receptor or Fc(epsilon)RI, respectively, and the inhibitory receptor Fc(gamma)RIIB. Here we show that inhibitory signalling by Fc(gamma)RIIB does not require the SH2-domain-containing protein tyrosine phosphatase, SHP-1, in mast cells and results in the recruitment of the SH2-domain-containing inositol polyphosphate 5-Phosphatase, SHIP, to the tyrosine-phosphorylated 13-amino-acid inhibitory motif of Fc(gamma)RIIB in both B cells and mast cells. SHIP, by hydrolysing the 5-phosphate of phosphatidylinositol(3,4,5)P3 and inositol(1,3,4,5)P4, suggests a mechanism by which Fc(gamma)RIIB can inhibit calcium influx and downstream responses triggered by immune receptors.

  • role of the inositol phosphatase ship in negative regulation of the immune system by the receptor fc gamma riib
    Nature, 1996
    Co-Authors: Masao Ono, Jeffrey V. Ravetch, Silvia Bolland, Paul Tempst
    Abstract:

    Immune complexes are potent activators of inflammatory cells, triggering effector responses through the crosslinking of Fc receptors (FcRs) such as Fc(epsilon)RI or Fc(gamma)RIII. On B cells and mast cells, immune complexes are also negative regulators of activation triggered by antigen and Fc receptors, a consequence of coligation of the B-cell antigen receptor or Fc(epsilon)RI, respectively, and the inhibitory receptor Fc(gamma)RIIB. Here we show that inhibitory signalling by Fc(gamma)RIIB does not require the SH2-domain-containing protein tyrosine phosphatase, SHP-1, in mast cells and results in the recruitment of the SH2-domain-containing inositol polyphosphate 5-Phosphatase, SHIP, to the tyrosine-phosphorylated 13-amino-acid inhibitory motif of Fc(gamma)RIIB in both B cells and mast cells. SHIP, by hydrolysing the 5-phosphate of phosphatidylinositol(3,4,5)P3 and inositol(1,3,4,5)P4, suggests a mechanism by which Fc(gamma)RIIB can inhibit calcium influx and downstream responses triggered by immune receptors.

Masao Ono - One of the best experts on this subject based on the ideXlab platform.

  • requirement of sh2 containing protein tyrosine phosphatases shp 1 and shp 2 for paired immunoglobulin like receptor b pir b mediated inhibitory signal
    Journal of Experimental Medicine, 1998
    Co-Authors: Akito Maeda, Masao Ono, Mari Kurosaki, Toshiyuki Takai, Tomohiro Kurosaki
    Abstract:

    Paired immunoglobulin-like receptor B (PIR-B) (p91) molecule has been proposed to function as an inhibitory receptor in B cells and myeloid lineage cells. We demonstrate here that the cytoplasmic region of PIR-B is capable of inhibiting B cell activation. Mutational analysis of five cytoplasmic tyrosines indicate that tyrosine 771 in the motif VxYxxL plays the most crucial role in mediating the inhibitory signal. PIR-B–mediated inhibition was markedly reduced in the SH2-containing protein tyrosine phosphatases SHP-1 and SHP-2 double-deficient DT40 B cells, whereas this inhibition was unaffected in the inositol polyphosphate 5′-phosphatase SHIP-deficient cells. These data demonstrate that PIR-B can negatively regulate B cell receptor activation and that this PIR-B–mediated inhibition requires redundant functions of SHP-1 and SHP-2.

  • association of tyrosine phosphatases shp 1 and shp 2 inositol 5 phosphatase ship with gp49b1 and chromosomal assignment of the gene
    Journal of Biological Chemistry, 1998
    Co-Authors: Asato Kuroiwa, Masao Ono, Yumi Yamashita, Masanori Inui, Takae Yuasa, Akira Nagabukuro, Yoichi Matsuda, Toshiyuki Takai
    Abstract:

    We have analyzed the molecules participating in the inhibitory function of gp49B1, a murine type I transmembrane glycoprotein expressed on mast cells and natural killer cells, as well as the chromosomal location of its gene. As assessed by SDS-polyacrylamide gel electrophoresis and immunoblot analysis, tyrosine-phosphorylated, but not nonphosphorylated, synthetic peptides matching each of the two immunoreceptor tyrosine-based inhibitory motif (ITIM)-like sequences found in the cytoplasmic portion of gp49B1 associated with the ∼65-kDa tyrosine phosphatase SHP-1 and ∼70-kDa SHP-2 derived from RBL-2H3 cells. In addition, the phosphotyrosyl peptide matching the second ITIM-like sequence also bound the ∼145-kDa inositol polyphosphate 5-Phosphatase SHIP. Thus, it has been strongly suggested that the inhibitory nature of gp49B involves the recruitment of SHP-1, SHP-2, and SHIP for the delivery of inhibitory signal to the cell interior upon phosphorylation of tyrosine residues in their ITIMs. The gp49B gene has been found to be in the juxtaposition of its cognate gene, gp49A. The gene pair was shown to locate in the B4 band of mouse chromosome 10. In this region, no conserved linkage homology to human chromosome 19, where the genes for killer cell inhibitory receptors are found, has been identified.

  • role of the inositol phosphatase ship in negative regulation of the immune system by the receptor feγriib
    Nature, 1996
    Co-Authors: Jeffrey V. Ravetch, Masao Ono, Silvia Olland, Paul Temps
    Abstract:

    IMMUNE complexes are potent activators of inflammatory cells, triggering effector responses through the crosslinking of Fc receptors (FcRs) such as FcΣRI or FcγRIII (ref. 1). On B cells and mast cells, immune complexes are also negative regulators of activation triggered by antigen and Fc receptors, a consequence of coligation of the B-cell antigen receptor or FcΣRI, respectively, and the inhibitory receptor FcγRIIB. Here we show that inhibitory signalling by FcγRIIB does not require the SH2-domain-containing protein tyrosine phosphatase, SHP-1, in mast cells and results in the recruitment of the SH2-domain-containing inositol polyphosphate 5-Phosphatase, SHIP, to the tyrosine-phosphorylated 13-amino-acid inhibitory motif of FcγRIIB in both B cells and mast cells. SHIP, by hydrolysing the 5-phosphate of phosphatidylinositol(3,4,5)P3 and inositol(l,3,4,5)P4, suggests a mechanism by which FcγRIIB can inhibit calcium influx and downstream responses triggered by immune receptors.

  • role of the inositol phosphatase ship in negative regulation of the immune system by the receptor feγriib
    Nature, 1996
    Co-Authors: Masao Ono, Jeffrey V. Ravetch, Silvia Bolland, Paul Tempst
    Abstract:

    Immune complexes are potent activators of inflammatory cells, triggering effector responses through the crosslinking of Fc receptors (FcRs) such as Fc(epsilon)RI or Fc(gamma)RIII. On B cells and mast cells, immune complexes are also negative regulators of activation triggered by antigen and Fc receptors, a consequence of coligation of the B-cell antigen receptor or Fc(epsilon)RI, respectively, and the inhibitory receptor Fc(gamma)RIIB. Here we show that inhibitory signalling by Fc(gamma)RIIB does not require the SH2-domain-containing protein tyrosine phosphatase, SHP-1, in mast cells and results in the recruitment of the SH2-domain-containing inositol polyphosphate 5-Phosphatase, SHIP, to the tyrosine-phosphorylated 13-amino-acid inhibitory motif of Fc(gamma)RIIB in both B cells and mast cells. SHIP, by hydrolysing the 5-phosphate of phosphatidylinositol(3,4,5)P3 and inositol(1,3,4,5)P4, suggests a mechanism by which Fc(gamma)RIIB can inhibit calcium influx and downstream responses triggered by immune receptors.

  • role of the inositol phosphatase ship in negative regulation of the immune system by the receptor fc gamma riib
    Nature, 1996
    Co-Authors: Masao Ono, Jeffrey V. Ravetch, Silvia Bolland, Paul Tempst
    Abstract:

    Immune complexes are potent activators of inflammatory cells, triggering effector responses through the crosslinking of Fc receptors (FcRs) such as Fc(epsilon)RI or Fc(gamma)RIII. On B cells and mast cells, immune complexes are also negative regulators of activation triggered by antigen and Fc receptors, a consequence of coligation of the B-cell antigen receptor or Fc(epsilon)RI, respectively, and the inhibitory receptor Fc(gamma)RIIB. Here we show that inhibitory signalling by Fc(gamma)RIIB does not require the SH2-domain-containing protein tyrosine phosphatase, SHP-1, in mast cells and results in the recruitment of the SH2-domain-containing inositol polyphosphate 5-Phosphatase, SHIP, to the tyrosine-phosphorylated 13-amino-acid inhibitory motif of Fc(gamma)RIIB in both B cells and mast cells. SHIP, by hydrolysing the 5-phosphate of phosphatidylinositol(3,4,5)P3 and inositol(1,3,4,5)P4, suggests a mechanism by which Fc(gamma)RIIB can inhibit calcium influx and downstream responses triggered by immune receptors.