Syndecan-2 Mediates Adhesion and Proliferation of Colon Carcinoma Cells

Park, Haein; Kim, Yeon-Hee; Lim, Yeunhwan; Han, Inn-Oc; Oh, Eok Soo

doi:10.1074/jbc.m202435200

Cited by 155 publications

(140 citation statements)

References 40 publications

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“…Normal colon epithelial cells did not express SDC2, whereas colon carcinoma cells showed SDC2 up-regulation resulting in an increased SDC2 expression that proved crucial for tumourigenicity. 9,11,14 Park et al 14 showed SDC2 to be necessary for cell-cycle progression and cell-matrix interaction in colon cancer cells. Moreover, an increased level of SDC2 led to a less adhesive phenotype and loss of contact inhibition.…”

Section: Syndecan-2 In Prostate Cancermentioning

confidence: 99%

“…7 Early recognizable role of SDC2 was cell adhesion and migration, but recently SDC2 has also been implicated in the tyrosine kinase signalling pathway activation, cancer progression, and angiogenesis. [8][9][10][11][12] Several studies investigated the role of SDC2 in different carcinomas; [13][14][15] however, only one was focused on SDC2 in prostate cancer. 16 SDC2 expression and relationship with established prognostic features were assessed in a cohort of 86 patients treated with radical prostatectomy for clinically localized prostate adenocarcinoma to determine the expression and prognostic value of SDC2 in prostate cancer.…”

Section: Introductionmentioning

confidence: 99%

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Expression and prognostic role of syndecan-2 in prostate cancer

Popović

Demirović

Spajić

et al. 2009

Prostate Cancer Prostatic Dis

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Syndecans are a four-member family of transmembrane heparan sulphate proteoglycans that have different functions in cell signalling, adhesion, cytoskeleton organization, migration, proliferation, and angiogenesis. Several studies investigated the role of syndecan-2 (SDC2) in different carcinomas; however, only one being focused on SDC2 in prostate cancer. SDC2 expression and relationship with established prognostic features were assessed in a cohort of 86 patients treated with radical prostatectomy for clinically localized prostate adenocarcinoma. SDC2 expression was present in the majority of prostate cancers and absent in only 11.6% of cases. SDC2 expression was also recorded in cells of prostatic intraepithelial neoplasia, whereas normal prostatic epithelial tissue and stroma did not express SDC2. SDC2 overexpression in prostate cancer was significantly associated with established features indicative of worse prognosis such as higher preoperative PSA (P ¼ 0.011), higher Gleason score (Po0.001), positive surgical margins (Po0.003), and extraprostatic extension of disease (Po0.003). Moreover, expression of SDC2 was also associated with biochemical disease progression on univariate analysis (Po0.001). Study results supported the potential role of SDC2 in prostatic carcinogenesis and cancer progression. Moreover, SDC2 could serve as an additional prognostic marker that might help in further stratifying the risk of disease progression in patients with prostate cancer.

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Section: Syndecan-2 In Prostate Cancermentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Expression and prognostic role of syndecan-2 in prostate cancer

Popović

Demirović

Spajić

et al. 2009

Prostate Cancer Prostatic Dis

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“…The activities of the extracellular domain also extend to other syndecans. Colon carcinoma cells plated in serum are induced to round up and detach when treated with soluble extracellular domain of syndecan-2, presumably because the soluble ectodomain disrupts an adhesion complex at the cell surface (8). Additionally, fibroblast growth factor 2-stimulated proliferation in the developing wing bud and cultured chondrocytes is blocked by antibodies against the syndecan-3 extracellular domain, suggesting a role for this protein domain in the assembly of the fibroblast growth factor 2 signaling complex (18,19).…”

mentioning

confidence: 99%

Syndecan-1 Transmembrane and Extracellular Domains Have Unique and Distinct Roles in Cell Spreading

McQuade

Rapraeger

2003

Journal of Biological Chemistry

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Raji cells expressing syndecan-1 (Raji-S1) adhere and spread when plated on heparan sulfate-binding extracellular matrix ligands or monoclonal antibody 281.2, an antibody directed against the syndecan-1 extracellular domain. Cells plated on monoclonal antibody 281.2 initially extend a broad lamellipodium, a response accompanied by membrane ruffling at the cell margin. Membrane ruffling then becomes polarized, leading to an elongated cell morphology. Previous work demonstrated that the syndecan-1 cytoplasmic domain is not required for these activities, suggesting important roles for the syndecan-1 transmembrane and/or extracellular domains in the assembly of a signaling complex necessary for spreading. Work described here demonstrates that truncation of the syndecan-1 extracellular domain does not affect the initial lamellipodial extension in the Raji-S1 cells but does inhibit the active membrane ruffling that is necessary for cell polarization. Replacement of the entire syndecan-1 transmembrane domain with leucine residues completely blocks the cell spreading. These data demonstrate that the syndecan-1 transmembrane and extracellular domains have important but distinct roles in Raji-S1 cell spreading; the extracellular domain mediates an interaction that is necessary for dynamic cytoskeletal rearrangements whereas an interaction of the transmembrane domain is required for the initial spreading response.The syndecans, a family of four cell surface heparan sulfate proteoglycans, are expressed on all adherent cells with roles including growth factor signaling, lipoprotein catabolism, and cell-cell and cell-matrix adhesion (1). Via their heparan sulfate glycosaminoglycan chains, the syndecans bind growth factors and their receptors, microbes, viruses, lipoproteins, proteases, and extracellular matrix proteins (2, 3). The syndecans are thought to act as matrix co-receptors with integrins to mediate cell binding and signaling on ligands that contain both heparan sulfate and integrin-binding motifs (3, 4). For example, fibroblasts plated on fibronectin adhere and spread via integrins, but binding of syndecan-4 is required for focal adhesion assembly. Syndecans, however, are also able to mediate adhesion and spreading when acting as the sole adhesion receptor, suggesting that the syndecan core proteins alone are able to mediate the assembly of signaling complexes that regulate adhesion and cell spreading (5-8). Here, the respective contributions of the syndecan cytoplasmic, transmembrane, and extracellular domains in the assembly of these signaling complexes remain unclear.The prime candidate to transduce syndecan-mediated signals is the cytoplasmic domain. Two regions of the cytoplasmic domain, C1 and C2, are highly conserved across species and across the four family members. The membrane proximal C1 region has been suggested to bind members of the FERM family of adaptor molecules, shown by the binding of syndecans-1 and -2 with ezrin (9). Ezrin bridges syndecan-2 with the cytoskeleton and regulates membrane protrusive...

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“…Syndecan expression has been reported to be altered during tumorigenesis and disease progression (30,36,39), enhancing interest in syndecan family heterodimerization. Analyzing the role of the conserved phenylalanine in heterodimerization may be useful in assessing the mechanism underlying these interactions and determining strategies to inhibit syndecan heterodimers.…”

Section: Discussionmentioning

confidence: 99%

The Conserved Phenylalanine in the Transmembrane Domain Enhances Heteromeric Interactions of Syndecans

Kwon

Park

Jang

et al. 2016

Journal of Biological Chemistry

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The transmembrane domain (TMD) of the syndecans, a family of transmembrane heparin sulfate proteoglycans, is involved in forming homo-and heterodimers and oligomers that transmit signaling events. Recently, we reported that the unique phenylalanine in TMD positively regulates intramolecular interactions of syndecan-2. Besides the unique phenylalanine, syndecan-2 contains a conserved phenylalanine (SDC2-Phe-169) that is present in all syndecan TMDs, but its function has not been determined. We therefore investigated the structural role of SDC2-Phe-169 in syndecan TMDs. Replacement of SDC2-Phe-169 by tyrosine (S2F169Y) did not affect SDS-resistant homodimer formation but significantly reduced SDS-resistant heterodimer formation between syndecan-2 and -4, suggesting that SDC2-Phe-169 is involved in the heterodimerization/ oligomerization of syndecans. Similarly, in an in vitro binding assay, a syndecan-2 mutant (S2(F169Y)) showed a significantly reduced interaction with syndecan-4. FRET assays showed that heteromolecular interactions between syndecan-2 and -4 were reduced in HEK293T cells transfected with S2(F169Y) compared with syndecan-2. Moreover, S2(F169Y) reduced downstream reactions mediated by the heterodimerization of syndecan-2 and -4, including Rac activity, cell migration, membrane localization of PKC␣, and focal adhesion formation. The conserved phenylalanine in syndecan-1 and -3 also showed heterodimeric interaction with syndecan-2 and -4. Taken together, these findings suggest that the conserved phenylalanine in the TMD of syndecans is crucial in regulating heteromeric interactions of syndecans.Integral membrane receptors consist of an extracellular domain that binds specific ligands, a transmembrane domain (TMD) 2 that transmits signals in response to ligand binding, and a cytoplasmic domain to which the signals are transmitted by the TMD and that is thereby activated, resulting in a conformational change that causes binding or induction of enzymatic activity inside the cell (1, 2). The TMD is therefore critically important in transmitting signals from the external environment to the inside of the cell, with many recent investigations exploring the mechanism by which TMD interactions regulate cell signaling (2-6). TMDs of single-pass membrane receptors have been shown to cluster, resulting in homotypic and/or heterotypic interactions, with TMDs often forming not only homo-and/or heterodimers but higher-order oligomers in cell membranes (7-10). Most investigations of TMD interactions have analyzed homo-oligomerization in vitro and in vivo, with fewer to date assessing heterotypic TMD associations.One of the most investigated examples of hetero-oligomerization in biology involves the family of EGF receptors, also called the ErbB family (11-13). Although only four ErbB family members have been identified to date, ErbB1 (EGF receptor), ErbB2 (HER2, Neu), ErbB3 (HER3), and ErbB4 (HER4), they have been shown to form 28 homo-and heterodimers (12). These combinations are thought to result in diverse cellul...

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Syndecan-2 Mediates Adhesion and Proliferation of Colon Carcinoma Cells

Cited by 155 publications

References 40 publications

Expression and prognostic role of syndecan-2 in prostate cancer

Expression and prognostic role of syndecan-2 in prostate cancer

Syndecan-1 Transmembrane and Extracellular Domains Have Unique and Distinct Roles in Cell Spreading

The Conserved Phenylalanine in the Transmembrane Domain Enhances Heteromeric Interactions of Syndecans

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