Fibronectin receptor integrins are involved in mast cell activation

Ra, Chisei; Yasuda, Masahiko; Yagita, Hideo; Okumura, Katsuhiko

doi:10.1016/0091-6749(94)90139-2

Cited by 73 publications

(67 citation statements)

References 12 publications

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“…For example, it is known that adherence of RBL-2H3 cells to fibronectin-coated surfaces enhances degranulation and serves as a costimulus for cytokine production (27)(28)(29). Similarly, cell activation by antigen-mediated clustering of IgE-Fc RI causes increased adhesion and spreading in mast cells (30,31).…”

Section: Discussionmentioning

confidence: 99%

Focal adhesion proteins connect IgE receptors to the cytoskeleton as revealed by micropatterned ligand arrays

Torres

Vasudevan

Holowka

et al. 2008

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

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Patterned surfaces that present specific ligands in spatially defined arrays are used to examine structural linkages between clustered IgE receptors (IgE-Fc RI) and the cytoskeleton in rat basophilic leukemia (RBL) mast cells. We showed with fluorescence microscopy that cytoskeletal F-actin concentrates in the same regions as cell surface IgE-Fc RI that bind to the micrometer-size patterned ligands. However, the proteins mediating these cytoskeletal connections and their functional relevance were not known. We now show that whereas the adaptor proteins ezrin and moesin do not detectably concentrate with the array of clustered IgE-Fc RI, focal adhesion proteins vinculin, paxillin, and talin, which are known to link F-actin with integrins, accumulate in these regions on the same time scale as F-actin. Moreover, colocalization of these focal adhesion proteins with clustered IgE-Fc RI is enhanced after addition of fibronectin-RGD peptides. Significantly, the most prominent rat basophilic leukemia cell integrin (␣5) avoids the patterned regions occupied by the ligands and associates preferentially with exposed regions of the silicon substrate. Thus, spatial separation provided by the patterned surface reveals that particular focal adhesion proteins, which connect to the actin cytoskeleton, associate with ligand-cross-linked IgE-Fc RI, independently of integrins. We investigated the functional role of one of these proteins, paxillin, in IgE-Fc RI-mediated signaling by using small interfering RNA. From these results, we determine that paxillin reduces stimulated phosphorylation of the Fc RI ␤ subunit but enhances stimulated Ca 2؉ release from intracellular stores. The results suggest that paxillin associated with clustered IgE-Fc RI has a net positive effect on Fc RI signaling.FceRI ͉ Lyn ͉ nanobiotechnology ͉ paxillin ͉ supported lipid bilayers C ells have evolved to respond to their chemical and physical environment. Chemical stimulants in the form of soluble or surface-bound ligands are recognized by specific cell surface receptors, and physical cues are sensed by integrins that bind to extracellular matrix proteins on surrounding substrates (1). Cross-talk between intracellular signaling pathways that are initiated by integrins and by ligand receptors has been clearly demonstrated, although spatial aspects of these processes have not been defined. Surfaces patterned on the micrometer scale offer the opportunity to separate regions that bind integrins from those that present ligands to cell surface receptors and thereby delineate respective cytoskeletal connections.The subject of our study is the IgE receptor (Fc RI), which is a member of the family of multisubunit immune recognition receptors that includes antigen receptors on B cells and T cells. This family of receptors has conserved structural features and similarly initiates intracellular signaling in response to multivalent ligands (antigens) that activate cells by clustering cell surface receptors. Fc RI receptors are found primarily in mast cells and basophi...

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Section: Discussionmentioning

confidence: 99%

Focal adhesion proteins connect IgE receptors to the cytoskeleton as revealed by micropatterned ligand arrays

Torres

Vasudevan

Holowka

et al. 2008

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

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“…Adhesion of MC to these extracellular proteins is dependent upon the activation state of the cell. Naive bone marrow-derived cultured MC or peritoneal MC require prior stimulation to activate the integrins necessary to adhere to extracellular matrix proteins (2,4,5). However, the human MC line HMC-1 has been reported to constitutively express active VLA-4 and VLA-5, the integrins that mediate the interaction of these cells with FN, and adhesion of these cells to FN is integrin dependent (6) Thus, HMC-1 cells provide a model of an activated human MC, as may exist in an inflammatory state.…”

Section: Ast Cells (Mc)mentioning

confidence: 99%

“…For example, Ag-induced histamine secretion can be potentiated when RBL-2H3 cells are bound to FN, and this potentiation can be blocked by Abs to VLA-4, VLA-5, and vitronectin receptor integrins (1,2). In the MC line, mast cell protease 5/1 stimulation with Ag at concentrations insufficient to cause significant mediator release markedly enhances cell adhesion to FN (9).…”

Section: Ast Cells (Mc)mentioning

confidence: 99%

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Inhibition of Calpain Is a Component of Nitric Oxide-Induced Down-Regulation of Human Mast Cell Adhesion

Forsythe

Befus

2003

The Journal of Immunology

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Nitric oxide is an important messenger that regulates mast cell activity by modifications to gene expression and intracellular pathways associated with exocytosis and adhesion. Integrin interactions with extracellular matrix components modulate an array of cell activities, including mediator production and secretion. To investigate the molecular mechanisms underlying NO regulation of mast cell function, we studied its effects on adhesion of a human mast cell line (HMC-1) to fibronectin (FN). The NO donors S-nitrosoglutathione and S-nitroso-N-acetylpenicillamine strongly down-regulated the adhesion of HMC-1 to FN. Inhibitors of soluble guanylate cyclase and protein kinase G did not alter the response of cells to NO. A peroxynitrite scavenger did not affect modulation of adhesion by NO, nor could the effect of NO be mimicked by the peroxynitrite-producing compound 3-morpholinosydnonimine. NO donors inhibited the cysteine protease, calpain, while calpain inhibitors mimicked the effect of NO and led to a decrease in the ability of HMC-1 cells to adhere to FN. Thus, NO is an effective down-regulator of human mast cell adhesion. The mechanism for this action does not involve peroxynitrite or activation of soluble guanylate cyclase. Instead, a portion of NO-induced down-regulation of adhesion may be attributed to inhibition of the cysteine protease, calpain, an enzyme that has been associated with control of integrin activation in other cell types. The inhibition of calpain is most likely mediated via nitrosylation of its active site thiol group. Calpain may represent a novel therapeutic target for the regulation of mast cell activity in inflammatory disorders.

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“…Antigenic stimulation of mast cells by cross-linking of the Fc⑀RI leads to release of various mediators which cause clinical phenomena associated with an allergic response (1,2). Adhesion of mast cells to the extracellular matrixcomponent fibronectin through very late Ag (VLA) 3 -5, an ␣ 5 ␤ 1 integrin, enhances the release of allergic mediators (3)(4)(5). The observation that VLA-5 can modulate mast cell degranulation makes this receptor a possible target for future therapeutic strategies against allergy and is the topic of the current study.…”

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confidence: 99%

Attenuation of Very Late Antigen-5-Mediated Adhesion of Bone Marrow-Derived Mast Cells to Fibronectin by Peptides with Inverted Hydropathy to EF-Hands

Broeke

Blalock

Villain

et al. 2001

The Journal of Immunology

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Release of allergic mediators from mast cells is enhanced by very late Ag (VLA)-5-mediated interaction of these cells with fibronectin. In this report, we show that VLA-5-mediated adhesion of bone marrow-derived mast cells to fibronectin can be induced by two different pathways: first, FcεRI clustering, which depends on calmodulin activation and extracellular Ca2+, and, second, by Mn2+ stimulation, which is independent of calmodulin activation and antagonized by Ca2+. Previous studies have shown the presence of several cation-binding domains in VLA-5 that are homologous to the calcium-binding EF-hands of calmodulin. To show a role for EF-hands of different proteins in VLA-5-mediated adhesion, we used calcium-like peptides (CALP), CALP1 and CALP2, designed to bind to EF-hands based on inverted hydropathy. CALP1 and, more potently, CALP2 inhibited FcεRI-induced adhesion to fibronectin via different mechanisms. The target for the effects of CALP1 and 2 on FcεRI-induced adhesion and degranulation was intracellular and likely involved calmodulin. Interestingly only CALP2 was able to inhibit Mn2+-induced calmodulin-independent adhesion by interfering with an extracellular target, which is probably VLA-5. We conclude that CALP1 and 2 can inhibit VLA-5-mediated adhesion of mast cells to fibronectin through binding to EF-hands of multiple proteins, and that these peptides can be used as lead compounds for the development of future therapy against allergy.

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Fibronectin receptor integrins are involved in mast cell activation

Cited by 73 publications

References 12 publications

Focal adhesion proteins connect IgE receptors to the cytoskeleton as revealed by micropatterned ligand arrays

Focal adhesion proteins connect IgE receptors to the cytoskeleton as revealed by micropatterned ligand arrays

Inhibition of Calpain Is a Component of Nitric Oxide-Induced Down-Regulation of Human Mast Cell Adhesion

Attenuation of Very Late Antigen-5-Mediated Adhesion of Bone Marrow-Derived Mast Cells to Fibronectin by Peptides with Inverted Hydropathy to EF-Hands

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