Syndecan-1 regulates αvβ5 integrin activity in B82L fibroblasts

McQuade, Kyle J.; Beauvais, Deanna Lee M.; Burbach, Brandon J.; Rapraeger, Alan C.

doi:10.1242/jcs.02970

Cited by 102 publications

(88 citation statements)

References 74 publications

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“…The Sdc1 regulates the activities of several integrins, including ␣v␤3, ␣v␤5, and ␤4 integrins. [43][44][45][46] Although the FN matrix assembly appears to be initiated mainly by Arg-Gly-Asp-binding integrin ␣5␤1, 47,48 alternative FN-binding integrin receptors (eg, ␣v␤3, ␣4␤1, and ␣v␤1) can also support this process once properly activated. 33,49 -52 It is possible that Sdc1 induction activates integrins other than ␣5␤1 and initiates an alternative assembly pathway, thus resulting in an ECM that is structurally/compositionally different from that assembled under the control of ␣5␤1.…”

Section: Discussionmentioning

confidence: 99%

Syndecan-1 in Breast Cancer Stroma Fibroblasts Regulates Extracellular Matrix Fiber Organization and Carcinoma Cell Motility

Yang

Mosher

Seo

et al. 2011

The American Journal of Pathology

124

126

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Stromal fibroblasts of breast carcinomas frequently express the cell surface proteoglycan syndecan-1 (Sdc1). In human breast carcinoma samples, stromal Sdc1 expression correlates with an organized, parallel, extracellular matrix (ECM) fiber architecture. To examine a possible link between stromal Sdc1 and the fiber architecture, we generated bioactive cell-free three-dimensional ECMs from cultures of Sdc1-positive and Sdc1-negative murine and human mammary fibroblasts (termed ECM-Sdc1 and ECM-mock, respectively). Indeed, ECM-Sdc1 showed a parallel fiber architecture that contrasted markedly with the random fiber arrangement of ECM-mock. When breast carcinoma cells were seeded into the fibroblast-free ECMs, ECM-Sdc1, but not ECM-mock, promoted their attachment, invasion, and directional movement. We further evaluated the contribution of the structural/compositional modifications in ECM-Sdc1 on carcinoma cell behavior. By microcontact printing of culture surfaces, we forced the Sdc1-negative fibroblasts to produce ECM with parallel fiber organization, mimicking the architecture observed in ECM-Sdc1. We found that the fiber topography governs carcinoma cell migration directionality. Conversely, an elevated fibronectin level in ECM-Sdc1 was responsible for the enhanced attachment of the breast carcinoma cells. These observations suggest that Sdc1 expression in breast carcinoma stromal fibroblasts promotes the assembly of an architecturally abnormal ECM that is permissive to breast carcinoma directional migration and invasion. Epithelial-stromal interactions play crucial roles in directing mammary gland development and in maintaining normal tissue homeostasis. Conversely, during tumorigenesis, the stroma accelerates carcinoma growth and progression. The predominant cell type within the stromal compartment is the fibroblast, which synthesizes, organizes, and maintains a three-dimensional (3D) network of glycoproteins and proteoglycans known as the extracellular matrix (ECM). Normal stromal fibroblasts and their ECM are believed to exert an inhibitory constraint on tumor growth and progression. 1,2 Major alterations occur in the stromal fibroblasts and ECM during neoplastic transformation, giving rise to a permissive and supportive microenvironment for carcinomas. Compared with their quiescent normal counterpart, carcinoma-associated fibroblasts display an activated phenotype, which is characterized by the expression of smooth muscle markers, an enhanced proliferative and migratory potential, and altered gene expression profiles. Carcinoma-associated fibroblasts produce and deposit elevated amounts and abnormal varieties of ECM components. 3-5 Recent evidence 6,7 indicates that not only ECM composition but also ECM architecture are altered in carcinomas and that these changes may promote tumor progression. However, the contribution of these stromal modifications to tumor development and the molecular mechanisms and signaling events underlying these alterations are incompletely understood.

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Section: Discussionmentioning

confidence: 99%

Syndecan-1 in Breast Cancer Stroma Fibroblasts Regulates Extracellular Matrix Fiber Organization and Carcinoma Cell Motility

Yang

Mosher

Seo

et al. 2011

The American Journal of Pathology

124

126

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“…Sdc1 regulates the activation of avb3 and avb5 integrins on mammary carcinoma cells, fibroblasts and endothelial cells Beauvais et al, 2009;Beauvais and Rapraeger, 2003;McQuade et al, 2006). Activation of avb3 and/or avb5 integrin stimulates adhesion, spreading and migration of tumor and endothelial cells, with clear consequences on tumor progression.…”

Section: Introductionmentioning

confidence: 99%

“…Ligation and clustering of Sdc1, either on cells in suspension or bound to an immobilized ligand (Sdc1 antibody or VN), activates the avb3 and/or avb5 integrin, thus stimulating cell spreading and migration Beauvais et al, 2009;Beauvais and Rapraeger, 2003;McQuade et al, 2006). Silencing of human Sdc1 expression by species-specific siRNAs blocks integrin activation, which can be rescued by ectopic expression of either full-length mouse Sdc1 or the glycosylphosphatidylinositolanchored mouse Sdc1 ectodomain alone (GPI-S1ED) McQuade et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

“…Silencing of human Sdc1 expression by species-specific siRNAs blocks integrin activation, which can be rescued by ectopic expression of either full-length mouse Sdc1 or the glycosylphosphatidylinositolanchored mouse Sdc1 ectodomain alone (GPI-S1ED) McQuade et al, 2006). This traced the integrin activation site exclusively to the Sdc1 ectodomain and, using Sdc1 deletion mutants, to a 34 amino acid site lying between residues 88 and 121 .…”

Section: Introductionmentioning

confidence: 99%

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Syndecan-1 couples the insulin-like growth factor-1 receptor to inside-out integrin activation

Beauvais

Rapraeger

2010

Journal of Cell Science

104

144

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SummarySyndecan-1 (Sdc1) engages and activates the avb3 (and/or avb5) integrin when clustered in human carcinoma and endothelial cells. Although the engagement is extracellular, the activation mechanism is cytoplasmic. This talin-dependent, inside-out signaling pathway is activated downstream of the insulin-like growth factor-1 receptor (IGF1R), whose kinase activity is triggered by Sdc1 clustering. In vitro binding assays using purified receptors suggest that association of the Sdc1 ectodomain with the integrin provides a 'docking face' for IGF1R. IGF1R docking and activation of the associated integrin is blocked by synstatin (SSTN 92-119 ), a peptide derived from the integrin engagement site in Sdc1. IGF1R colocalizes with avb3 integrin and Sdc1 in focal contacts, but fails to associate with or activate the integrin in cells either lacking Sdc1 or expressing Sdc1 D67-121 , a mutant that is unable to form the Sdc1-integrin-IGF1R ternary complex. Integrin activation is also blocked by IGF1R inhibitors or by silencing IGF1R or talin expression with smallinterfering RNAs (siRNAs). In both cases, expression of the constitutively active talin F23 head domain rescues integrin activation.We recently reported that SSTN 92-119 blocks angiogenesis and impairs tumor growth in mice, therefore this Sdc1-mediated integrin regulatory mechanism might be a crucial regulator of disease processes known to rely on these integrins, including tumor cell metastasis and tumor-induced angiogenesis.

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“…Syndecan-1 is a heparan sulfate proteoglycan acting as a transmembrane receptor. Its coupling with other receptors such as integrins might induce cell adhesion and angiogenesis [12]. It was suggested that YKL-40 could activate key signaling cascades-PI3K/AKT and MAPK/ERK resulting in high rate of cell proliferation and tumor cell survival [13,14].…”

Section: Ykl-40 Ligandsmentioning

confidence: 99%

YKL‐40: The Search for New Biomarkers in Rheumatoid Arthritis

Kazakova¹,

Sarafian²

2017

New Developments in the Pathogenesis of Rheumatoid Arthritis

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There is a need for biomarkers to detect early joint inlammation and destruction of cartilage in diferent types of arthritis. YKL-40, a 39 kDa heparin-and chitin-binding secreted glycoprotein (also known as human cartilage gp39), has been recently discovered. Its exact biological function is still unclear. Speciic receptors for YKL-40 have not been identiied yet. The clinical signiicance of YKL-40 as a biomarker is discussed in diferent aspects. High level of YKL-40 is found in various human i`nlammatory and neoplastic diseases. We present a review highlighting the information available on YKL-40 and its signiicance in inlammatory joint diseases, like rheumatoid arthritis (RA). We also report original personal data on the topic concerning YKL-40 levels in serum and synovial luid of patients with RA in comparison with ultrasonographic parameters and cytokine levels. The indings suggest that YKL-40 might be implicated in the pathogenesis of the disease and could indicate the level of joint inlammation.

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Syndecan-1 regulates αvβ5 integrin activity in B82L fibroblasts

Cited by 102 publications

References 74 publications

Syndecan-1 in Breast Cancer Stroma Fibroblasts Regulates Extracellular Matrix Fiber Organization and Carcinoma Cell Motility

Syndecan-1 in Breast Cancer Stroma Fibroblasts Regulates Extracellular Matrix Fiber Organization and Carcinoma Cell Motility

Syndecan-1 couples the insulin-like growth factor-1 receptor to inside-out integrin activation

YKL‐40: The Search for New Biomarkers in Rheumatoid Arthritis

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