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  • 1
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    Online Resource
    Acute depletion of plasma membrane Phosphatidylinositol 4,5-bisphosphate impairs specific steps in G protein-coupled receptor endocytosis
    The Company of Biologists ; 2012
    In:  Journal of Cell Science
    Details
    In: Journal of Cell Science, The Company of Biologists
    Abstract: Receptor endocytosis plays an important role in regulating the responsiveness of cells to specific ligands. Phosphatidylinositol 4,5-bisphosphate (PtdInsP2) has been shown to be critical for endocytosis of some cell surface receptors, such as EGF and transferrin receptor, but its role in G protein-coupled receptor internalization has not been investigated. By employing luciferase-labeled type 1 angiotensin II (AT1), type 2C serotonin (5HT2C) or β2 adrenergic (β2A) receptors and fluorescently tagged proteins (β-arrestin 2, plasma membrane targeted Venus, Rab5) we were able to follow the sequence of molecular interactions along the endocytic route of the receptors in HEK 293 cells using the highly sensitive method of bioluminescence resonance energy transfer and confocal microscopy. To study the role of plasma membrane PtdInsP2 in receptor endocytosis, we used our previously developed rapamycin-inducible heterodimerization system, in which the recruitment of a 5-phosphatase domain to the plasma membrane degrades PtdInsP2. Here we show that ligand-induced interaction of AT1, 5HT2C and β2A receptors with β-arrestin 2 was unaffected by PtdInsP2 depletion. However, arrival of the receptors to Rab5-positive early endosomes was completely abolished in the absence of PtdInsP2. Remarkably, removal of the receptors from the plasma membrane was reduced but not eliminated after PtdInsP2 depletion. Under these conditions, stimulated AT1 receptors clustered along the plasma membrane but did not enter the cells. Our data suggest that in the absence of PtdInsP2, these receptors move into clathrin-coated membrane structures, but these are not cleaved efficiently and hence cannot reach the early endosomal compartment.
    Type of Medium: Online Resource
    ISSN: 1477-9137 , 0021-9533
    URL: Article
    DOI: 10.1242/jcs.097279
    Language: English
    Publisher: The Company of Biologists
    Publication Date: 2012
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  • 2
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    Acute depletion of plasma membrane phosphatidylinositol 4,5-bisphosphate impairs specific steps in endocytosis of the G-protein-coupled receptor
    The Company of Biologists ; 2012
    In:  Journal of Cell Science Vol. 125, No. 12 ( 2012-06-15), p. 3013-3013
    Details
    In: Journal of Cell Science, The Company of Biologists, Vol. 125, No. 12 ( 2012-06-15), p. 3013-3013
    Type of Medium: Online Resource
    ISSN: 1477-9137 , 0021-9533
    URL: Article
    DOI: 10.1242/jcs.115048
    Language: English
    Publisher: The Company of Biologists
    Publication Date: 2012
    detail.hit.zdb_id: 219171-4
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  • 3
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    Selective cellular effects of overexpressed pleckstrin-homology domains that recognize PtdIns(3,4,5)P3 suggest their interaction with protein binding partners
    The Company of Biologists ; 2005
    In:  Journal of Cell Science Vol. 118, No. 20 ( 2005-10-15), p. 4879-4888
    Details
    In: Journal of Cell Science, The Company of Biologists, Vol. 118, No. 20 ( 2005-10-15), p. 4879-4888
    Abstract: Several pleckstrin-homology (PH) domains with the ability to bind phosphatidylinositol (3,4,5)-trisphosphate [PtdIns(3,4,5)P3, PIP3] were expressed as green fluorescent protein (GFP) fusion proteins to determine their effects on various cellular responses known to be activated by PIP3. These proteins comprised the PH domains of Akt, ARNO, Btk or GRP1, and were found to show growth-factor-stimulated and wortmannin-sensitive translocation from the cytosol to the plasma membrane in several cell types, indicating their ability to recognize PIP3. Remarkably, although overexpressed Akt-PH–GFP and Btk-PH–GFP were quite potent in antagonizing the PIP3-mediated activation of the Akt protein kinase, such inhibition was not observed with the other PH domains. By contrast, expression of the PH domains of GRP1 and ARNO, but not of Akt or Btk, inhibited the attachment and spreading of freshly seeded cells to culture dishes. Activation of PLCγ by epidermal growth factor (EGF) was attenuated by the PH domains of GRP1, ARNO and Akt, but was significantly enhanced by the Btk PH domain. By following the kinetics of expression of the various GFP-fused PH domains for several days, only the PH domain of Akt showed a lipid-binding-dependent self-elimination, consistent with its interference with the anti-apoptotic Akt signaling pathway. Mutations of selective residues that do not directly participate in PIP3 binding in the GRP1-PH and Akt-PH domain were able to reduce the dominant-negative effects of these constructs yet retain their lipid binding. These data suggest that interaction with and sequestration of PIP3 may not be the sole mechanism by which PH domains interfere with cellular responses and that their interaction with other membrane components, most probably with proteins, allows a more specific participation in the regulation of specific signaling pathways.
    Type of Medium: Online Resource
    ISSN: 1477-9137 , 0021-9533
    URL: Article
    DOI: 10.1242/jcs.02606
    Language: English
    Publisher: The Company of Biologists
    Publication Date: 2005
    detail.hit.zdb_id: 219171-4
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  • 4
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    Inositol-lipid binding motifs: signal integrators through protein-lipid and protein-protein interactions
    The Company of Biologists ; 2005
    In:  Journal of Cell Science Vol. 118, No. 10 ( 2005-05-15), p. 2093-2104
    Details
    In: Journal of Cell Science, The Company of Biologists, Vol. 118, No. 10 ( 2005-05-15), p. 2093-2104
    Abstract: Inositol lipids have emerged as universal lipid regulators of protein signaling complexes in defined membrane compartments. The number of protein modules that are known to recognise these membrane lipids is rapidly increasing. Pleckstrin homology domains, FYVE domains, PX domains, ENTH domains, CALM domains, PDZ domains, PTB domains and FERM domains are all inositide-recognition modules. The latest additions to this list are members of the clathrin adaptor protein and arrestin families. Initially, inositol lipids were believed to recruit signaling molecules to specific membrane compartments, but many of the domains clearly do not possess high enough affinity to act alone as localisation signals. Another important notion is that some (and probably most) of these protein modules also have protein binding partners, and their protein- and lipid-binding activities might influence one another through allosteric mechanisms. Comparison of the structural features of these domains not only reveals a high degree of conservation of their lipid interaction sites but also highlights their evolutionary link to protein modules known for protein-protein interactions. Protein-protein interactions involving lipid-binding domains could serve as the basis for phosphoinositide-induced conformational regulation of target proteins at biological membranes. Therefore, these modules function as crucially important signal integrators, which explains their involvement in a broad range of regulatory functions in eukaryotic cells.
    Type of Medium: Online Resource
    ISSN: 1477-9137 , 0021-9533
    URL: Article
    DOI: 10.1242/jcs.02387
    Language: English
    Publisher: The Company of Biologists
    Publication Date: 2005
    detail.hit.zdb_id: 219171-4
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  • 5
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    Endosomal sorting of VAMP3 is regulated by PI4K2A
    The Company of Biologists ; 2014
    In:  Journal of Cell Science
    Details
    In: Journal of Cell Science, The Company of Biologists
    Abstract: Specificity of membrane fusion in vesicular trafficking is dependent on proper subcellular distribution of soluble N-ethylmaleimide sensitive factor attachment protein receptors (SNAREs). Although SNARE complexes are fairly promiscuous in vitro, significant specificity is achieved in cells due to spatial segregation and shielding of SNARE motifs prior to association with cognate Q-SNAREs. In this study we identified phosphatidylinositol 4-kinase IIα (PI4K2A) as a binding partner of vesicle-associated membrane protein 3 (VAMP3), a small R-SNARE involved in recycling and retrograde transport, and found that the two proteins co-reside on tubulo-vesicular endosomes. PI4K2A knockdown inhibited VAMP3 trafficking to perinuclear membranes and impaired the rate of VAMP3-mediated recycling of the transferrin receptor. Moreover, depletion of PI4K2A significantly decreased association of VAMP3 with its cognate Q-SNARE, Vti1a. Although binding of VAMP3 to PI4K2A did not require kinase activity, acute depletion of PtdIns4P on endosomes significantly delayed VAMP3 trafficking. Phospholipid modulation of SNARE function has been proposed based on in vitro studies and our study provides mechanistic evidence in support of these claims by identifying PI4K2A and PtdIns4P as regulators of an R-SNARE in intact cells.
    Type of Medium: Online Resource
    ISSN: 1477-9137 , 0021-9533
    URL: Article
    DOI: 10.1242/jcs.148809
    Language: English
    Publisher: The Company of Biologists
    Publication Date: 2014
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  • 6
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    EFR3s are palmitoylated plasma membrane proteins that control responsiveness to G protein-coupled receptors
    The Company of Biologists ; 2014
    In:  Journal of Cell Science
    Details
    In: Journal of Cell Science, The Company of Biologists
    Abstract: The yeast Efr3p protein is a major regulator of the Stt4p phosphatidylinositol 4-kinase at ER-PM contact sites. Its mutant fly homologue, Rbo displays diminishing light responses attributed to progressively impaired PLC signaling. Here we find that Efr3s play a role in maintaining responsiveness to angiotensin II (AngII) receptors. RNAi-mediated depletion of EFR3A and EFR3B impaired the sustained phase of cytosolic Ca2+ response to high concentration of AngII in HEK293 cells expressing the wild type but not a truncated AT1a receptor, missing the phosphorylation sites. Efr3 depletion had minimal effect on the recovery of plasma membrane phosphoinositides during stimulation, and AT1 receptors still underwent ligand-induced internalization. A higher level of basal receptor phosphorylation and a larger response was observed after stimulation. Moreover, Gq activation more rapidly desensitized after AngII stimulation in Efr3 downregulated cells. Similar but smaller effect of EFR3 depletion was observed on the desensitization of the cAMP response after isoproterenol stimulation. These data suggest that mammalian Efr3s contribute to the control of the phosphorylation state and hence desensitization of AT1a receptors and could affect GPCR responsiveness in higher eukaryotes.
    Type of Medium: Online Resource
    ISSN: 1477-9137 , 0021-9533
    URL: Article
    DOI: 10.1242/jcs.157495
    Language: English
    Publisher: The Company of Biologists
    Publication Date: 2014
    detail.hit.zdb_id: 219171-4
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  • 7
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    The dynamics of plasma membrane PtdIns(4,5) P 2 at fertilization of mouse eggs
    The Company of Biologists ; 2002
    In:  Journal of Cell Science Vol. 115, No. 10 ( 2002-05-15), p. 2139-2149
    Details
    In: Journal of Cell Science, The Company of Biologists, Vol. 115, No. 10 ( 2002-05-15), p. 2139-2149
    Abstract: A series of intracellular Ca2+ oscillations are responsible for triggering egg activation and cortical granule exocytosis at fertilization in mammals. These Ca2+ oscillations are generated by an increase in inositol 1,4,5-trisphosphate [Ins(1,4,5)P3], which results from the hydrolysis of phosphatidylinositol 4,5-bisphosphate[PtdIns(4,5)P2] . Using confocal imaging to simultaneously monitor Ca2+ and plasma membrane PtdIns(4,5)P2in single living mouse eggs we have sought to establish the relationship between the kinetics of PtdIns(4,5)P2 metabolism and the Ca2+ oscillations at fertilization. We report that there is no detectable net loss of plasma membrane PtdIns(4,5)P2either during the latent period or during the subsequent Ca2+oscillations. When phosphatidylinositol 4-kinase is inhibited with micromolar wortmannin a limited decrease in plasma membrane PtdIns(4,5)P2 is detected in half the eggs studied. Although we were unable to detect a widespread loss of PtdIns(4,5)P2, we found that fertilization triggers a net increase in plasma membrane PtdIns(4,5)P2 that is localized to the vegetal cortex. The fertilization-induced increase in PtdIns(4,5)P2 follows the increase in Ca2+, is blocked by Ca2+ buffers and can be mimicked, albeit with slower kinetics, by photoreleasing Ins(1,4,5)P3. Inhibition of Ca2+-dependent exocytosis of cortical granules, without interfering with Ca2+ transients, inhibits the PtdIns(4,5)P2 increase. The increase appears to be due to de novo synthesis since it is inhibited by micromolar wortmannin. Finally,there is no increase in PtdIns(4,5)P2 in immature oocytes that are not competent to extrude cortical granules. These studies suggest that fertilization does not deplete plasma membrane PtdIns(4,5)P2 and that one of the pathways for increasing PtdIns(4,5)P2 at fertilization is invoked by exocytosis of cortical granules.
    Type of Medium: Online Resource
    ISSN: 1477-9137 , 0021-9533
    URL: Article
    DOI: 10.1242/jcs.115.10.2139
    Language: English
    Publisher: The Company of Biologists
    Publication Date: 2002
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  • 8
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    Crucial role of phosphatidylinositol 4-kinase IIIα in development of zebrafish pectoral fin is linked to phosphoinositide 3-kinase and FGF signaling
    The Company of Biologists ; 2009
    In:  Journal of Cell Science Vol. 122, No. 23 ( 2009-12-01), p. 4303-4310
    Details
    In: Journal of Cell Science, The Company of Biologists, Vol. 122, No. 23 ( 2009-12-01), p. 4303-4310
    Abstract: Phosphatidylinositol 4-kinases (PI4Ks) catalyze the first committed step in the synthesis of phosphoinositides, important lipid regulators of signaling and trafficking pathways. Here we cloned Pik4a, one of the zebrafish PI4K enzymes, and studied its role(s) in vertebrate development using morpholino oligonucleotide-based gene silencing in zebrafish. Downregulation of Pik4a led to multiple developmental abnormalities, affecting the brain, heart, trunk and most prominently causing loss of pectoral fins. Strikingly similar defects were caused by treatment of the developing embryos with the phosphoinositide 3-kinase (PI3K) inhibitor, LY294002. To investigate the cause of the pectoral fin developmental defect, we focused on fibroblast growth factor (FGF) signaling pathways because vertebrate limb development requires the concerted action of a series of FGF ligands. Using in situ hybridization, the pectoral fin defect was traced to disruption of the early FGF signaling loops that are crucial for the establishment of the sharp signaling center formed by the apical ectodermal ridge and the underlying mesenchyme. This, in turn caused a prominent loss of the induction of one of the mitogen-activated protein kinase (MAPK) phosphatases, Mkp3, an essential intermediate in vertebrate limb development. These changes were associated with impaired proliferation in the developing fin bud due to a loss of balance between the MAPK and PI3K branch of FGF-initiated signals. Our results identify Pik4a as an upstream partner of PI3Ks in the signaling cascade orchestrated by FGF receptors with a prominent role in forelimb development.
    Type of Medium: Online Resource
    ISSN: 1477-9137 , 0021-9533
    URL: Article
    DOI: 10.1242/jcs.057646
    Language: English
    Publisher: The Company of Biologists
    Publication Date: 2009
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  • 9
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    Molecular anatomy of the early events in STIM1 activation; oligomerization or conformational change?
    The Company of Biologists ; 2017
    In:  Journal of Cell Science
    Details
    In: Journal of Cell Science, The Company of Biologists
    Abstract: Decreased luminal ER Ca2+ concentration triggers oligomerization and clustering of the ER Ca2+-sensor, STIM1 to promote its association with plasma membrane Orai1 Ca2+ channels leading to increased Ca2+ influx. A key step in STIM1 activation is the release of its SOAR domain from an intramolecular clamp formed with the STIM1 first coiled-coil (CC1) region. Using a truncated STIM1(1-343) molecule that captures or releases the isolated SOAR domain depending on luminal ER Ca2+ concentrations, we analyzed the early molecular events that control the intramolecular clamp formed between the CC1 and SOAR domains. We found that STIM1 forms constitutive dimers and its CC1 domain can bind SOAR of another STIM1 molecule in trans. Artificial oligomerization failed to liberate the SOAR domain, or activate STIM1 unless the luminal Ca2+ sensing domains were removed. We propose that the release of SOAR from its CC1 interaction is controlled by changes in the orientation of the two CC1 domains in STIM1 dimers. Ca2+ unbinding in the STIM1 luminal domains initiates the conformational change allowing SOAR domain liberation and clustering leading to Orai1 channel activation.
    Type of Medium: Online Resource
    ISSN: 1477-9137 , 0021-9533
    URL: Article
    DOI: 10.1242/jcs.205583
    Language: English
    Publisher: The Company of Biologists
    Publication Date: 2017
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  • 10
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    ORP3 phosphorylation regulates phosphatidylinositol 4-phosphate and Ca2+ dynamics at PM-ER contact sites
    The Company of Biologists ; 2020
    In:  Journal of Cell Science
    Details
    In: Journal of Cell Science, The Company of Biologists
    Abstract: Oxysterol-binding protein (OSBP)-related proteins (ORPs) mediate non-vesicular lipid-transfer between intracellular membranes. Phosphoinositide gradients play important roles in the ability of OSBP and some ORPs to transfer cholesterol and phosphatidylserine between the ER and other organelle membranes. Here we show that PM association of ORP3, a less characterized ORP family member, is triggered by PKC activation, especially when combined with Ca2+ increases and is determined by both PI(4,5)P2 and PI4P. After activation, ORP3 efficiently extracts PI4P and to a small extent phosphatidic acid from the PM and slightly increases PM cholesterol levels. Full activation of ORP3 results in decreased PM PI4P levels and inhibits Ca2+ entry via the store-operated Ca2+ entry pathway. The C-terminal region of ORP3 that follows the strictly defined lipid transfer domain, is found to be critical for the proper localization and function of the protein.
    Type of Medium: Online Resource
    ISSN: 1477-9137 , 0021-9533
    URL: Article
    DOI: 10.1242/jcs.237388
    Language: English
    Publisher: The Company of Biologists
    Publication Date: 2020
    detail.hit.zdb_id: 219171-4
    detail.hit.zdb_id: 1483099-1
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