Lipid rafts and little caves

Zajchowski, Laura D.; Robbins, Stephen M.

doi:10.1046/j.0014-2956.2001.02715.x

Cited by 214 publications

(46 citation statements)

References 188 publications

(251 reference statements)

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“…Although highly hypothetical for thrombin and APC, there are precedents for this mechanism of lipid raftassociated G protein-coupled receptor signaling in the literature (17). This mechanism, or other similar subtle signaling mechanisms facilitated by lipid rafts (17,18), may explain how thrombin and APC can function in opposite disruptive and protective pathways through the activation of the same receptor in endothelial cells. Thus, our findings that the receptors of both protein C activation and protective APC signaling pathways are colocalized in the membrane lipid rafts of endothelial cells pave the way for designing new approaches to understanding the details of this important question.…”

Section: Discussionmentioning

confidence: 99%

“…However, PAR-1 may or may not be colocalized with the other two receptors in the same lipid raft. A ligand-induced fusion of different lipid rafts can play a key role in cellular signal transduction mechanisms (17,18). The localization of PAR-1 in different lipid rafts, enriched with different G proteins and related downstream signaling molecules, can endow specificity for PAR-1 signaling through either the thrombin or APC pathways.…”

Section: Discussionmentioning

confidence: 99%

“…One possible explanation of why the endogenous APC can exert a more efficient cytoprotective effect in endothelial cells might be that protein C zymogen activation by the thrombin-TM complex and the subsequent PAR-1 signaling events take place in the same microenvironment on the membrane surface. For example, a variety of G protein-coupled receptor signaling molecules and tyrosine kinases are known to be compartmentalized within the cholesterol/glycosphingolipid-rich cell membrane lipid rafts and caveolae (17,18). In fact, there is some evidence for EPCR being targeted to such membrane microdomains as demonstrated by a higher rate of proteolytic shedding of soluble EPCR (sEPCR) in the caveolin-overexpressing cells (19).…”

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confidence: 99%

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Receptors of the protein C activation and activated protein C signaling pathways are colocalized in lipid rafts of endothelial cells

Bae

Yang

Rezaie

2007

Proc. Natl. Acad. Sci. U.S.A.

176

212

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Ever-increasing evidence in the literature suggests that the antiinflammatory and cytoprotective properties of activated protein C (APC) are mediated through its endothelial protein C receptor (EPCR)-dependent cleavage of protease-activated receptor 1 (PAR-1) on endothelial cells. However, recent results monitoring the cleavage rate of PAR-1 on human umbilical vein endothelial cells, transfected with an alkaline phosphatase-PAR-1 fusion reporter construct, have indicated that the catalytic activity of thrombin toward PAR-1 is several orders of magnitude higher than that of APC. Because thrombin is required for generation of APC, and because it also functions in the proinflammatory pathways through the activation of PAR-1, it has been difficult to understand how APC can elicit protective cellular responses through the activation of PAR-1 when thrombin is present. In this study we provide a plausible answer to this question by demonstrating that the critical receptors required for both protein C activation (thrombomodulin and EPCR) and APC cellular signaling (EPCR and PAR-1) pathways are colocalized in the membrane lipid rafts in endothelial cells. We further show that the APC cleavage of PAR-1 on cells transfected with a PAR-1 cleavage reporter construct is not sensitive to the cofactor function of EPCR. Thus, the colocalization of EPCR and PAR-1 in lipid rafts is a key requirement for the cellular signaling activity of APC. Thrombomodulin colocalization with these receptors on the same membrane microdomain can also recruit thrombin to activate the EPCR-bound protein C, thereby eliciting PAR-1 signaling events that are involved in the APC protective pathways. endothelial protein C receptor ͉ protease-activated receptor 1 ͉ thrombin ͉ thrombomodulin

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Receptors of the protein C activation and activated protein C signaling pathways are colocalized in lipid rafts of endothelial cells

Bae

Yang

Rezaie

2007

Proc. Natl. Acad. Sci. U.S.A.

176

212

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“…HA, which represents ϳ35% of the total glycosaminoglycans in the adult mammalian brain (42), was recently found endocytosed in membrane regions termed lipid rafts (43), in which a significant portion of one of its receptor CD44 molecules were identified (22,44). Because specialized plasma membrane domains such as lamellipodia and caveolae dictate some of the characteristics of glioma invasion (45,46), the identification and functional characterization of specific molecular players located within these domains should provide further insight into their role in interacting with ECM proteins.…”

Section: Discussionmentioning

confidence: 99%

Hyaluronan Cell Surface Binding Is Induced by Type I Collagen and Regulated by Caveolae in Glioma Cells

Annabi

Thibeault

Moumdjian

et al. 2004

Journal of Biological Chemistry

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Hyaluronan (HA) is a component of the brain extracellular matrix environment that is synthesized and secreted by glioma cells. The primary cell surface receptor for HA is CD44, a membrane glycoprotein that is functionally regulated by a membrane type 1 matrix metalloproteinase (MT1-MMP). Both CD44 and MT1-MMP are partially located in Triton X-100-insoluble domains, but no functional link has yet been established between them. In the present study, we studied the regulation of HA cell surface binding in U-87 glioma cells. We show that an MMP-dependent mechanism regulates the intrinsic cell surface binding of HA as ilomastat, a broad MMP inhibitor, increased HA binding to glioma cells. HA binding was also rapidly and specifically up-regulated by 3-fold by type I collagen in U-87 cells, which also induced a significant morphological reorganization associated with the activation of a latent form of MMP-2 through a MT1-MMP-mediated mechanism. Interestingly, caveolae depletion with a cell surface cholesteroldepleting agent ␤-cyclodextrin triggered an additional increase (9-fold) in the binding of HA, in synergy with type I collagen. On the other hand, HA cell surface binding was diminished by the MEK inhibitor PD98059 and by the overexpression of a recombinant, wild type MT1-MMP, whereas its cytoplasmic-deleted form had no effect. Taken together, our results suggest that MT1-MMP regulates, through its cytoplasmic domain, the cell surface functions of CD44 in a collagen-rich pericellular environment. Additionally, we describe a new molecular mechanism regulating the invasive potential of glioma cells involving a MT1-MMP/CD44/caveolin interaction, which could represent a potential target for anti-cancer therapies.The principal molecules that have been identified in the normal brain extracellular matrix (ECM) 1 are hyaluronan (HA; also known as hyaluronic acid, hyaluronate) and chondroitin sulfate (1, 2). HA is an important glycosaminoglycan constituent believed to be implicated in angiogenesis, the formation of new blood vessels from preexisting vasculature. Although the serum level of HA is already used as an indicator of progressive malignant disease (3), its effects on in vivo angiogenesis and endothelial cell (EC) function are complex and have been reported to depend on HA concentration and molecular size (4, 5). Accordingly, whereas high molecular weight HA was shown to inhibit EC functions (6), low molecular weight HA stimulated EC proliferation, tubulogenesis (6, 7), and neovascularization (8). Moreover, small HA polymers efficiently regulated CD44 cell surface functional expression and promoted tumor cell migration (9). Astrocytic tumors of the central nervous system express CD44 among other cell adhesion receptors of the integrin or immunoglobulin superfamily. Although HA is the principal ligand of CD44, other CD44 ligands include the ECM components collagen, fibronectin, laminin, and chondroitin sulfate, whereas mucosal addressin, serglycin, osteopontin, and the class II invariant chain represent ECM-unrelat...

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“…In our previous work, we referred to these membrane microdomains as caveolae-like domains, because the LAN-1 cells expressed both caveolin-1 and -2. However, since we have only characterized this membrane fraction based on its detergent insolubility and low buoyant density fractionation, it is more appropriate to refer to these domains as lipid rafts, consistent with recent nomenclature (36).…”

Section: Identification Of Frs2 As a Lipid Raft-associated Protein-mentioning

confidence: 99%

Fibroblast Growth Factor-2-induced Signaling through Lipid Raft-associated Fibroblast Growth Factor Receptor Substrate 2 (FRS2)

Ridyard¹,

Robbins

2003

Journal of Biological Chemistry

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The plasma membrane is not homogenous but contains specific subcompartments characterized by their unique lipid and protein composition. Based on their enrichment in various signaling molecules, these membrane microdomains are recognized to be sites of localized signal transduction for a number of extracellular stimuli. We have previously shown that fibroblast growth factor-2 (FGF2) induced a specific signaling response within a lipid raft membrane microdomain in human neuroblastoma cells characterized by the tyrosine phosphorylation of a p80 phosphoprotein. Herein, we show that this protein is the signaling adaptor FRS2 and that it is localized exclusively to lipid rafts in vitro and in vivo. We have examined how the tyrosine phosphorylation and serine-threonine phosphorylation of FRS2 within lipid rafts affect the response of cells to FGF2 signaling. Our data suggest that activation of protein kinase C, Src family kinases, and MEK1/2 are involved in regulating serine-threonine phosphorylation of FRS2, which can indirectly affect FRS2 phosphotyrosine levels. We also show that Grb2 is recruited to lipid rafts during signaling events and that activation of MEK1/2 by different mechanisms within lipid rafts may lead to different cellular responses. This work suggests that compartmentalized signaling within lipid rafts may provide a level of specificity for growth factor signaling.

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Lipid rafts and little caves

Cited by 214 publications

References 188 publications

Receptors of the protein C activation and activated protein C signaling pathways are colocalized in lipid rafts of endothelial cells

Receptors of the protein C activation and activated protein C signaling pathways are colocalized in lipid rafts of endothelial cells

Hyaluronan Cell Surface Binding Is Induced by Type I Collagen and Regulated by Caveolae in Glioma Cells

Fibroblast Growth Factor-2-induced Signaling through Lipid Raft-associated Fibroblast Growth Factor Receptor Substrate 2 (FRS2)

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