The syndecan-1 ectodomain regulates αvβ3 integrin activity in human mammary carcinoma cells

Beauvais, DeannaLee M.; Burbach, Brandon J.; Rapraeger, Alan C.

doi:10.1083/jcb.200404171

Cited by 219 publications

(229 citation statements)

References 73 publications

(93 reference statements)

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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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“…A site within the ectodomain of syndecan-4 interacts with an unidentified surface molecule to promote adhesion without requiring the cytoplasmic domain (36). The integrin ␣v␤3 was shown to be dependent on syndecan-1 for activation and to mediate signals required for human mammary carcinoma cell spread on vitronectin (37). Recently, Whiteford and Couchman (38) have shown that a conserved NXIP motif is required for cell adhesion properties of the syndecan-4 ectodomain.…”

Section: Discussionmentioning

confidence: 99%

A Peptide Derived from Tenascin-C Induces β1 Integrin Activation through Syndecan-4

Saito

Imazeki

Miura

et al. 2007

Journal of Biological Chemistry

116

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Tenascin-C (TN-C) is unique for its cell adhesion modulatory function. We have shown that TNIIIA2, a synthetic 22-mer peptide derived from TN-C, stimulated ␤1 integrinmediated cell adhesion of nonadherent and adherent cell types, by inducing activation of ␤1 integrin. The active site of TNIIIA2 appeared cryptic in the TN-C molecule but was exposed by MMP-2 processing of TN-C. The following results suggest that cell surface heparan sulfate (HS) proteoglycan (HSPG), including syndecan-4, participated in TNIIIA2-induced ␤1 integrin activation: 1) TNIIIA2 bound to cell surface HSPG via its HS chains, as examined by photoaffinity labeling; 2) heparitinase I treatment of cells abrogated ␤1 integrin activation induced by TNIIIA2; 3) syndecan-4 was isolated by affinity chromatography using TNIIIA2-immobilized beads; 4) small interfering RNA-based down-regulation of syndecan-4 expression reduced TNIIIA2-induced ␤1 integrin activation, and consequent cell adhesion to fibronectin; 5) overexpression of syndecan-4 core protein enhanced TNIIIA2-induced activation of ␤1 integrin. However, treatments that targeted the cytoplasmic region of syndecan-4, including ectopic expression of its mutant truncated with the cytoplasmic domains and treatment with protein kinase C␣ inhibitor Gö6976, did not influence the TNIIIA2 activity. These results suggest that a TNIIIA2-related matricryptic site of the TN-C molecule, exposed by MMP-2 processing, may have bound to syndecan-4 via its HS chains and then induced conformational change in ␤1 integrin necessary for its functional activation. A lateral interaction of ␤1 integrin with the extracellular region of the syndecan-4 molecule may be involved in this conformation change. Tenascin (TN)-C2 is one of the most intriguing extracellular matrix (ECM) proteins (1-3). TN-C is expressed predominantly during embryogenesis, wound healing, and neoplastic processes, in which alternative mRNA splicing within the fibronectin (FN) type III-like (FN-III) repeats can generate different TN-C isoforms (4). Multifunctional properties have been identified for TN-C, including effects on cell adhesion, migration, proliferation, survival, and differentiation. The effects of TN-C on cell adhesion are particularly complex; the TN-C substrate supports attachment of some cell types, but is nonadhesive or even repulsive for other cell types (5-7). Based on these antipodal effects on cell adhesion, TN-C is multifunctional and is therefore classified as an adhesion modulatory ECM protein, a so-called "matricellular" protein (8). Various TN-C molecule domains, especially FN-III repeats, including the alternative splicing domains, have been implicated in its function as a matricellular protein. However, their contributions to the adhesion modulatory effects of TN-C are not completely understood.Interactions of cells with the ECM are largely mediated by members of the integrin superfamily of adhesive receptors. The most unique feature of integrins is their ability to alter ligand binding and signaling activities. Because ...

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“…33 Integrins have heparan-binding domains, which indicate that heparan sulfate proteoglycans may modulate integrin signaling and cell adhesion. 34 Movement/rotation problems in the chondrocytes of the growth plate have been reported in b1-integrin-null mice. 33 The b1-integrin-null growth plates show larger and round-shaped proliferating chondrocytes arranged side by side, possibly reflecting impaired movement and inability to form columns.…”

Section: Cilia In Growth Plate and Osteochondroma Ce De Andrea Et Almentioning

confidence: 99%

Primary cilia organization reflects polarity in the growth plate and implies loss of polarity and mosaicism in osteochondroma

Andrea

Wiweger

Prins

et al. 2010

Laboratory Investigation

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Primary cilia are specialized cell surface projections found on most cell types. Involved in several signaling pathways, primary cilia have been reported to modulate cell and tissue organization. Although they have been implicated in regulating cartilage and bone growth, little is known about the organization of primary cilia in the growth plate cartilage and osteochondroma. Osteochondromas are bone tumors formed along the growth plate, and they are caused by mutations in EXT1 or EXT2 genes. In this study, we show the organization of primary cilia within and between the zones of the growth plate and osteochondroma. Using confocal and electron microscopy, we found that in both tissues, primary cilia have a similar formation but a distinct organization. The shortest ciliary length is associated with the proliferative state of the cells, as confirmed by Ki-67 immunostaining. Primary cilia organization in the growth plate showed that nonpolarized chondrocytes (resting zone) are becoming polarized (proliferating and hypertrophic zones), orienting the primary cilia parallel to the longitudinal axis of the bone. The alignment of primary cilia forms one virtual axis that crosses the center of the columns of chondrocytes reflecting the polarity axis of the growth plate. We also show that primary cilia in osteochondromas are found randomly located on the cell surface. Strikingly, the growth plate-like polarity was retained in sub-populations of osteochondroma cells that were organized into small columns. Based on this, we propose the existence of a mixture ('mosaic') of normal lining (EXT þ /À or EXT wt/wt ) and EXT À/À cells in the cartilaginous cap of osteochondromas.

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The syndecan-1 ectodomain regulates αvβ3 integrin activity in human mammary carcinoma cells

Cited by 219 publications

References 73 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

A Peptide Derived from Tenascin-C Induces β1 Integrin Activation through Syndecan-4

Primary cilia organization reflects polarity in the growth plate and implies loss of polarity and mosaicism in osteochondroma

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