Fibulin-5 binds human smooth-muscle cells through α5β1 and α4β1 integrins, but does not support receptor activation

Lomas, Amanda; Mellody, Kieran T.; Freeman, Lyle J.; Bax, Daniel V.; Shuttleworth, C. Adrian; Kielty, Cay M.

doi:10.1042/bj20070400

Cited by 79 publications

(85 citation statements)

References 40 publications

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“…The level of cell adhesion to human tropoelastin (68%) is consistent with the level of cell attachment observed on other elastic fiber proteins such as fibulin-5 (45% adhesion (35)) and fibrillin-rich microfibrils (35% adhesion (36)). Therefore, human tropoelastin is a truly cell adhesive protein.…”

Section: Discussionsupporting

confidence: 64%

“…Therefore, it is unlikely that fibulin-5 will bind to this small section of tropoelastin, making it unlikely that fibulin-5 is acting as a bridging molecule for cell adhesion. In addition, potential bridging proteins associated with elastic fibers, namely fibrillin-1 (41), fibulin-5 (40), and MAGP-2 (42), bind to cells via RGD motifs (36,35,43). As we observed no inhibition of cell binding to human tropoelastin by RGD peptides, it is unlikely that these proteins act as bridging proteins between cells and human tropoelastin.…”

Section: Discussioncontrasting

confidence: 37%

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Cell Adhesion to Tropoelastin Is Mediated via the C-terminal GRKRK Motif and Integrin αVβ3

Bax

Rodgers

Bilek

et al. 2009

Journal of Biological Chemistry

151

181

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Elastin fibers are predominantly composed of the secreted monomer tropoelastin. This protein assembly confers elasticity to all vertebrate elastic tissues including arteries, lung, skin, vocal folds, and elastic cartilage. In this study we examined the mechanism of cell interactions with recombinant human tropoelastin. Cell adhesion to human tropoelastin was divalent cation-dependent, and the inhibitory anti-integrin ␣ V ␤ 3 antibody LM609 inhibited cell spreading on tropoelastin, identifying integrin ␣ V ␤ 3 as the major fibroblast cell surface receptor for human tropoelastin. Cell adhesion was unaffected by lactose and heparin sulfate, indicating that the elastin-binding protein and cell surface glycosaminoglycans are not involved. The C-terminal GRKRK motif of tropoelastin can bind to cells in a divalent cation-dependent manner, identifying this as an integrin binding motif required for cell adhesion.

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Section: Discussionsupporting

confidence: 64%

Section: Discussioncontrasting

confidence: 37%

Cell Adhesion to Tropoelastin Is Mediated via the C-terminal GRKRK Motif and Integrin αVβ3

Bax

Rodgers

Bilek

et al. 2009

Journal of Biological Chemistry

151

181

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“…Having established that the assembly of extensive microfibril arrays is suppressed whenever α5β1-integrin-mediated fibronectin fibrillogenesis is disrupted, we investigated whether fibronectinindependent activation of β1 integrins can directly rescue microfibril assembly, using fibronectin-depleted cultures incubated with the integrin-β1-activating antibody TS2/16 at a concentration (10 μg/ml) that activates β1-integrin-mediated signalling (Lomas et al, 2007), or with mouse IgG as a control. RT-PCR results indicated that fibronectin was significantly reduced by RNAi (P=0.0027) and neither TS2/16 nor a mouse IgG control stimulated fibronectin expression (not shown).…”

Section: Activation Of β1 Integrins In Fibronectin-depleted Cultures mentioning

confidence: 99%

Fibrillin-1 microfibril deposition is dependent on fibronectin assembly

Kinsey

Williamson

Chaudhry

et al. 2008

Journal of Cell Science

125

131

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Newly deposited microfibrils strongly colocalise with fibronectin in primary fibroblasts. Microfibril formation is grossly inhibited by fibronectin depletion, but rescued by supplementation with exogenous cellular fibronectin. As integrin receptors are key determinants of fibronectin assembly, we investigated whether they also influenced microfibril deposition. Analysis of β1-integrin-receptor-null fibroblasts, blockage of cell surface integrin receptors that regulate fibronectin assembly and disruption of Rho kinase all result in suppressed deposition of both fibronectin and microfibrils. Antibody activation of β1 integrins in fibronectin-depleted cultures is insufficient to rescue microfibril assembly. In fibronectinRGE/RGE mutant mouse fibroblast cultures, which do not engage α5β1 integrin, extracellular assembly of both fibronectin and microfibrils is markedly reduced. Thus, pericellular microfibril assembly is regulated by fibronectin fibrillogenesis.

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“…In addition to stabilizing elastic fibers, Fbln5 functions as a molecular rheostat that regulates processes such as cell proliferation and migration in a cell type-specific manner (21)(22)(23). For example, Fbln5 blocks FN-mediated integrin signaling in smooth muscle cells (24). Our laboratory has identified a unique function for Fbln5 in pancreatic tumors.…”

mentioning

confidence: 99%

Hypoxia and Transforming Growth Factor β Cooperate to Induce Fibulin-5 Expression in Pancreatic Cancer

Topalovski¹,

Hagopian²,

Wang

et al. 2016

Journal of Biological Chemistry

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The deposition of extracellular matrix (ECM) is a defining feature of pancreatic ductal adenocarcinoma (PDA), where ECM signaling can promote cancer cell survival and epithelial plasticity programs. However, ECM signaling can also limit PDA tumor growth by producing cytotoxic levels of reactive oxygen species. For example, excess fibronectin stimulation of ␣5␤1 integrin on stromal cells in PDA results in reduced angiogenesis and increased tumor cell apoptosis because of oxidative stress. Fibulin-5 (Fbln5) is a matricellular protein that blocks fibronectin-integrin interaction and thus directly limits ECMdriven reactive oxygen species production and supports PDA progression. Compared with normal pancreatic tissue, Fbln5 is expressed abundantly in the stroma of PDA; however, the mechanisms underlying the stimulation of Fbln5 expression in PDA are undefined. Using in vitro and in vivo approaches, we report that hypoxia triggers Fbln5 expression in a TGF-␤-and PI3K-dependent manner. Pharmacologic inhibition of TGF-␤ receptor, PI3K, or protein kinase B (AKT) was found to block hypoxia-induced Fbln5 expression in mouse embryonic fibroblasts and 3T3 fibroblasts. Moreover, tumor-associated fibroblasts from mouse PDA were also responsive to TGF-␤ receptor and PI3K/AKT inhibition with regard to suppression of Fbln5. In genetically engineered mouse models of PDA, therapy-induced hypoxia elevated Fbln5 expression, whereas pharmacologic inhibition of TGF-␤ signaling reduced Fbln5 expression. These findings offer insight into the signaling axis that induces Fbln5 expression in PDA and a potential strategy to block its production.The maintenance of solid tumors relies heavily on cues received from the surrounding environment. The ECM 2 is composed of structural proteins such as FN and collagen, which promote signaling through integrins and receptor tyrosine kinases (1, 2). ECM signaling is modulated by matricellular proteins, which regulate ECM-cell interactions without serving a direct structural function (3-5). The composition of the ECM is dynamic and varies between tumors and tumor types, contributing to intra-and intertumor heterogeneity, which presents challenges for effective therapeutic strategies. Furthermore, mouse studies have revealed anti-and pro-tumorigenic functions for ECM (5-7). In addition to ECM, stromal cells, including endothelial cells, immune cells, and fibroblasts, are present in the tumor microenvironment. These cells contribute to tumor growth, invasion, and chemoresponse (8 -10).During tumor progression, cancer cells release factors that maintain a microenvironment conducive for growth. For example, TGF-␤ is a cytokine expressed in many cancers that enhances the expression of multiple ECM molecules, including but not limited to FN, collagen, elastin, and fibulins (11-13). Fbln5 is a 448-amino acid secretory glycoprotein of the fibulin family of matricellular proteins. Fbln5 is unique among its members as it contains an RGD-integrin binding domain and can ligate a number of integrins (14). Fbln5 is ex...

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Fibulin-5 binds human smooth-muscle cells through α5β1 and α4β1 integrins, but does not support receptor activation

Cited by 79 publications

References 40 publications

Cell Adhesion to Tropoelastin Is Mediated via the C-terminal GRKRK Motif and Integrin αVβ3

Cell Adhesion to Tropoelastin Is Mediated via the C-terminal GRKRK Motif and Integrin αVβ3

Fibrillin-1 microfibril deposition is dependent on fibronectin assembly

Hypoxia and Transforming Growth Factor β Cooperate to Induce Fibulin-5 Expression in Pancreatic Cancer

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