Syndecan-4 Modulates Focal Adhesion Kinase Phosphorylation

Wilcox-Adelman, Sarah A.; Denhez, Fabienne; Goetinck, Paul F.

doi:10.1074/jbc.m201283200

Cited by 123 publications

(101 citation statements)

References 98 publications

(88 reference statements)

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“…The compact conformation of FN dimers is maintained by intramolecular interactions involving the type III 12-14 repeats of FN. 53,54 The type III [12][13][14] repeats, also known as heparin II binding domain, interact with the HS chains from various members of the Sdc family. 55 Binding of Sdc1 with heparin II may facilitate unfolding of dimeric FNs and expose FN self-assembly (FN-binding) sites, thus promoting FN deposition and fibrillogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…Concomitant engagement of Sdc4 and integrins promotes Rho GTPase and focal adhesion kinase (FAK) activities, which are crucial for efficient initiation of FN matrix assembly. [12][13][14][15] Sdc1 is expressed primarily by epithelial and plasma cells of healthy adult tissue. 16 Recently, we and others 17,18 observed the induction of Sdc1 in stromal fibroblasts of invasive breast carcinomas.…”

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confidence: 99%

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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%

mentioning

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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“…Signaling through RhoA GTPase is required for maximal fibrin-FN matrix contraction and expression of syndecan-4 contributes to the activation of RhoA (Wilcox-Adelman et al, 2002). We bypassed syndecan-4 and stimulated RhoA by treatment of syndecan-4 -null cells with lysophosphatidic acid (LPA).…”

Section: K S Midwood Et Almentioning

confidence: 99%

“…Syndecan-4 -deficient mouse dermal fibroblasts were seeded at a density of 1 ϫ 10 5 cells per 35-mm culture dish in antibiotic-free DMEM plus 10% fetal bovine serum. After 24 h at 37°C, cells were transfected with a pcDNA3.1 expression vector containing rat syndecan-4 cDNA (kindly provided by Dr. Paul Goetinck; Wilcox-Adelman et al, 2002) plus a pcDNA3-GFP expression vector (gift from Dr. Donald Winkelmann, Robert Wood Johnson Medical School) as a transfection reporter in LipofectAMINE 2000 reagent and OptiMem medium. In parallel, cells were transfected with the pcDNA3-GFP vector alone.…”

Section: Transfectionmentioning

confidence: 99%

“…However, antibodies treated with a blocking peptide had no effect on matrix contraction ( Figure 3B). This function-blocking antibody also reduced the extent of cell spreading on fibrin-FN matrix (our unpublished results).Signaling through RhoA GTPase is required for maximal fibrin-FN matrix contraction and expression of syndecan-4 contributes to the activation of RhoA (Wilcox-Adelman et al, 2002). We bypassed syndecan-4 and stimulated RhoA by treatment of syndecan-4 -null cells with lysophosphatidic acid (LPA).…”

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confidence: 99%

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Coregulation of Fibronectin Signaling and Matrix Contraction by Tenascin-C and Syndecan-4

Midwood

Valenick

Hsia

et al. 2004

MBoC

133

139

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Syndecan-4 is a ubiquitously expressed heparan sulfate proteoglycan that modulates cell interactions with the extracellular matrix. It is transiently up-regulated during tissue repair by cells that mediate wound healing. Here, we report that syndecan-4 is essential for optimal fibroblast response to the three-dimensional fibrin-fibronectin provisional matrix that is deposited upon tissue injury. Interference with syndecan-4 function inhibits matrix contraction by preventing cell spreading, actin stress fiber formation, and activation of focal adhesion kinase and RhoA mediated-intracellular signaling pathways. Tenascin-C is an extracellular matrix protein that regulates cell response to fibronectin within the provisional matrix. Syndecan-4 is also required for tenascin-C action. Inhibition of syndecan-4 function suppresses tenascin-C activity and overexpression of syndecan-4 circumvents the effects of tenascin-C. In this way, tenascin-C and syndecan-4 work together to control fibroblast morphology and signaling and regulate events such as matrix contraction that are essential for efficient tissue repair. INTRODUCTIONTissue architecture is defined by the three-dimensional (3D) organization of the proteins and proteoglycans that comprise the extracellular matrix (ECM). Individual ECM components influence cell arrangements and activities through binding to transmembrane receptors, thus initiating intracellular signaling and altering gene expression and other downstream events. Tissues undergo continual maintenance and remodeling through controlled deposition and removal of specific ECM components. These changes in ECM composition and organization modulate cell behaviors and serve important roles throughout development and in the adult during both physiological and pathological processes (Lukashev and Werb, 1998).The provisional matrix that forms at sites of tissue injury undergoes extensive remodeling and turnover during wound repair. Composed predominantly of covalently cross-linked fibrin and plasma fibronectin (FN), this fibrin-FN provisional matrix coordinates the activities of cells involved in wound repair. It is remodeled over time to recapitulate normal tissue and this remodeling involves cellmediated contraction and deposition of new FN-rich matrix (Clark, 1996;Midwood et al., 2004). FN, a major component of the matrix, is a ubiquitously expressed, multifunctional extracellular glycoprotein that promotes cell adhesion. It controls many intracellular pathways and influences a wide range of cell functions (Hynes, 1990). For example, FN within a 3D fibrin-FN provisional matrix initiates signaling via focal adhesion kinase (FAK) and RhoA in order to promote fibroblast spreading, stress fiber formation, and focal adhesion assembly (Wenk et al., 2000;.The provisional matrix contacts many other ECM proteins that are induced at different stages of tissue repair, including thrombospondins, SPARC, and tenascin-C. These proteins are specifically up-regulated at wound sites where they modulate cell-ECM interactions (re...

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microRNA‐140‐3p modulates invasiveness, motility, and extracellular matrix adhesion of breast cancer cells by targeting syndecan‐4

Onyeisi

Greve

Espinoza-Sánchez

et al. 2021

J of Cellular Biochemistry

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Syndecan-4, a predicted target of the microRNA miR-140-3p, plays an important role in multiple steps of tumor progression and is the second most abundant heparan sulfate proteoglycan produced by breast carcinoma cell lines. To investigate the potential functional relationship of miR-140-3p and syndecan-4, MDA-MB-231, SKBR3, and MCF-7 breast cancer (BC) cells were transiently transfected with pre-miR-140-3p, syndecan-4 small interfering RNAJ, or control reagents, respectively. Altered cell behavior was monitored by adhesion, migration, and invasion chamber assays. Moreover, the prognostic value of syndecan-4 was assessed by Kaplan-Maier Plotter analysis of gene expression data from tumor samples of 4929 patients. High expression of syndecan-4 was associated with better relapse-free survival in the whole collective of BC patients, but correlated with a worse survival in the subgroup of estrogen receptor negative and estrogen/progesterone-receptor negative patients. miR-140-3p expression was associated with improved survival irrespective of hormone receptor status. miR-140-3p overexpression induced posttranscriptional downregulation of syndecan-4, as demonstrated by quantitative real-time PCR (qPCR), flow cytometry, and luciferase assays, resulting in decreased BC cell migration and matrigel invasiveness. Furthermore, miR-140-3p overexpression and syndecan-4 silencing increased the adhesion of BC to fibronectin and laminin. qPCR analysis demonstrated that syndecan-4 silencing leads to altered gene expression of adhesion-related molecules, such as fibronectin and focal adhesion kinase, as well as in the gene expression of the proinvasive factors matrix metalloproteinase 2 and heparanase (also known as HPSE). We conclude that syndecan-4 is a novel target of miR-140-3p that regulates BC cell invasiveness and cell-matrix interactions in the tumor microenvironment.This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

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Syndecan-4 Modulates Focal Adhesion Kinase Phosphorylation

Cited by 123 publications

References 98 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

Coregulation of Fibronectin Signaling and Matrix Contraction by Tenascin-C and Syndecan-4

microRNA‐140‐3p modulates invasiveness, motility, and extracellular matrix adhesion of breast cancer cells by targeting syndecan‐4

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