The role of syndecans in disease and wound healing

Fears, Constance Y.; Woods, Anne

doi:10.1016/j.matbio.2006.07.003

Cited by 136 publications

(112 citation statements)

References 169 publications

(237 reference statements)

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“…The ability of the TMD to drive detergent-resistant oligomerization of syndecan-3 (22) has led to the expectation that all syndecans self-associate strongly through their TMDs (7,(17)(18)(19)35). Given the 48-72% pairwise sequence identity between paralog TMDs and the strict conservation of a GxxxG dimerization motif, it might seem that all syndecan TMDs would support the same interactions.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Transmembrane domains of the syndecan family of growth factor coreceptors display a hierarchy of homotypic and heterotypic interactions

Dews

MacKenzie

2007

Proc. Natl. Acad. Sci. U.S.A.

105

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The single-pass transmembrane domains (TMDs) of the syndecan family of cell surface adhesion molecules have been implicated in functional protein-protein interactions. Although each paralog contains a conserved GxxxG dimerization motif, we show here that the syndecan-1 TMD dimerizes weakly, the syndecan-3 and syndecan-4 TMDs each dimerize strongly, and the syndecan-2 TMD dimerizes very strongly. These markedly different levels of selfassociation suggest that paralog TMDs play different roles in directing functional interactions of each full-length syndecan family member. We further show that each syndecan TMD forms detergent-resistant heteromeric complexes with other paralogs, and that these interactions exhibit selectivity. Although heteromeric interactions among full-length syndecan paralogs have not been reported, we argue that the distinct hierarchy of proteinprotein interactions mediated by the syndecan TMDs may give rise to considerable complexity in syndecan function. The demonstration that TMD homodimerization and heterodimerization can be mediated by GxxxG motifs and modulated by sequence context has implications for the signaling mechanisms of other cell surface receptors, including the integrins and the erbB family.homodimerization ͉ heterodimerization ͉ selectivity S yndecans are cell surface receptors that participate in cellcell and cell-matrix interactions critical to animal development. In mammals, where four syndecan paralogs exist (1-5), syndecan expression is tissue-specific and developmentally regulated, with most cells expressing one or more syndecans (6, 7). Syndecan-1 plays roles in early development (8-10) and wound healing (11), and syndecan-2 participates in neuronal dendritic spine morphogenesis (12), angiogenic sprouting (13), and Xenopus left/right axis formation (14). Syndecan-3 is involved in skeletogenesis (15), and syndecan-4 participates in the formation of integrin-containing focal adhesions (16). Although our knowledge of the mechanisms underlying syndecan biology is still sparse, it is already clear that understanding syndecan function has implications for treatment of cancer, wound healing, and viral and bacterial pathogenesis (reviewed in ref. 17).Each syndecan contains an ectodomain, a transmembrane domain (TMD), and a short, C-terminal cytoplasmic domain. Syndecan family members interact with a wide array of partners: the divergent heparan sulfate-modified ectodomains bind matrix proteins and growth factors, and the cytosolic domains bind cytoskeletal proteins and PDZ-domain proteins through the C1 and C2 regions (reviewed in refs. 18 and 19). Syndecan TMDs are also thought to make functional interactions: some functions of syndecan-2 and syndecan-4 depend on self-association through their TMDs (20), and the TMD of syndecan-1 makes interactions that lead to the initial spreading response of Raji cells (21). The first evidence of TMD involvement in syndecan protein-protein interactions was the attribution of detergentresistant noncovalent oligomerization of the syndecan-3 ...

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Section: Discussionmentioning

confidence: 99%

“…Although our knowledge of the mechanisms underlying syndecan biology is still sparse, it is already clear that understanding syndecan function has implications for treatment of cancer, wound healing, and viral and bacterial pathogenesis (reviewed in ref. 17).…”

mentioning

confidence: 99%

Transmembrane domains of the syndecan family of growth factor coreceptors display a hierarchy of homotypic and heterotypic interactions

Dews

MacKenzie

2007

Proc. Natl. Acad. Sci. U.S.A.

105

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“…[14][15][16][17][18] Therefore, AG73-labeled polyethyleneglycol-modified liposomes (AG73-PEG liposomes) were prepared, which were capable of encapsulating a gene condensed by poly-L-lysine.…”

mentioning

confidence: 99%

“…[11][12][13] It has been reported that syndecan-2 is highly expressed in various cancer cells and play a role in angiogenesis. [14][15][16][17][18] Therefore, AG73-labeled polyethyleneglycol-modified liposomes (AG73-PEG liposomes) were prepared, which were capable of encapsulating a gene condensed by poly-L-lysine.…”

mentioning

confidence: 99%

Preparation and Characterization of Laminin-Derived Peptide AG73-Coated Liposomes as a Selective Gene Delivery Tool

Negishi

Omata

Iijima

et al. 2010

Biological & Pharmaceutical Bulletin

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In gene therapy, it is necessary that the development of delivery vehicles or vectors can selectively deliver therapeutic genes to target cells safely and with high efficiency. There are two main approaches in gene delivery, viral gene delivery and non-viral gene delivery. Although viral vector have high transfection efficiencies over a wide range of cell targets, they have major limitations, including virally-induced inflammatory responses and oncogenic effects.1,2) Non-viral vectors, which are generally delivered as a complex with chemical and/or biochemical vectors such as cationic lipids or polymers, continue to be an attractive alternative to viral vectors due to their safety, versatility, and ease of preparation and scale-up. Non-viral vectors, however, generally suffer from relatively low transfection efficiencies. 3,4) Selective gene therapy approaches have been considered as a promising cure for various cancers. Therefore, it is necessary to develop delivery vehicles that can selectively deliver therapeutic genes to target cancer cells safely and with high efficiency. Several different targeting moieties have been used in studies on cancer gene therapy, such as transferrin, folate, anisamide, RGD-peptide, and antibodies. [5][6][7][8][9][10] In this context, the present study focused on AG73 peptide, which is 12 amino acid synthetic peptide derived from the globular domain of the laminin a1 chain. AG73 peptide is as a ligand for syndecans, one of the major heparin sulfatecontaining transmembrane protein.11-13) It has been reported that syndecan-2 is highly expressed in various cancer cells and play a role in angiogenesis. [14][15][16][17][18] Therefore, AG73-labeled polyethyleneglycol-modified liposomes (AG73-PEG liposomes) were prepared, which were capable of encapsulating a gene condensed by poly-L-lysine.In this study, we assessed the characterization and transfection efficiency of prepared AG73-PEG liposomes. To confirm the conjugation of AG73 peptide to liposomes and the morphology of AG73-PEG liposomes, we performed highperformance liquid chromatography (HPLC) analysis and electron microscopy observation. Furthermore, we examined whether AG73-PEG liposomes can deliver genes to cells selectively via syndecan-2. MATERIALS AND METHODS MaterialsThe plasmid pCytomegalovirus (CMV)-Luc is an expression vector encoding the firefly luciferase gene under the control of a cytomegalovirus promoter.Cell Lines and Cultures A 293T human embryonic kidney carcinoma cell line, stably overexpressing syndecan-2 (293T-Syn2), was cultured in Dulbecco's modified Eagle's medium (DMEM; Kohjin Bio Co., Ltd., Tokyo, Japan), supplemented with 10% fetal bovine serum (FBS; Equitech Bio Inc., Kerrville, TX, U.S.A.), penicillin (100 U/ml), Streptomycin (100 mg/ml), and puromycin (0.4 mg/ml), at 37°C in an humidified 5% CO 2 atmosphere.Preparation of AG73-PEG Liposomes The Cys-AG73 peptide (CGG-RKRLQVQLSIRT) and scrambled Cys-AG73T control peptide (CGG-LQQRRSVLRTKI) were synthesized manually using the 9-fluorenylmethoxycarbonyl (F...

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“…These changes play important roles in tumor pathophysiology (Beauvais and Rapraeger, 2004;Sanderson, 2001;Fears and Woods, 2006). It has been suggested that syndecan-1 is involved in Wnt-1 induced tumor in the mouse mammary gland (Alexander et al, 2000).…”

Section: Soluble Syndecans and Tumormentioning

confidence: 99%

Syndecan as a Messenger to Link Diabetes and Cancer

Kim

Raman²

2011

Biomolecules and Therapeutics

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Cell surface syndecans are membrane-anchored proteoglycans. These glycoproteins have covalently linked glycosaminoglycan side chains. They interact via their extracellular part with various growth factors, extracellular matrix components, other cell surface molecules, and proteins involved in the regulation of blood coagulation. Thus the syndecans involve in synchronized expression patterns during embryogenesis and malignant transformation. These cell-cell interactions via their extracellular matrix ligands control cell proliferation, dynamic cytoskeletal remodeling, apoptosis and gene expression.Over the last few years, it has been widely accepted that heparan sulfate proteoglycans play a role in growth control, cell spreading, cellular recognition, cellular adhesion, and signaling, possibly as co -receptors with integrins, IGF-1R and cell -cell adhesion molecules, including fi bronectin, vitronectin, laminins, and the fi brillar collagens (Bernfi eld et al., 1999;Woods, 2001;Alexopoulou et al., 2007;Beauvais and Rapraeger, 2010). In addition, all syndecans have dibasic peptide sequence adjacent to the plasma membrane. Thus, the extracellular domains of syndecans could be cleaved by extracellular proteases. Syndecan's ectodomains have been shown to regulate a multitude of biological functions in celldependent and cell-independent approaches (Li et al., 2002;Endo et al., 2003;Elenius et al., 2004). Soluble syndecans also convert the membrane-bound receptors into soluble effectors/or antagonists. The soluble ectodomains of syndecans can compete with intact syndecans for extracellular ligands (Steinfeld et al., 1996). In this review, we will discuss the general Syndecans are membrane-anchored proteoglycans and implicated in the pathogenesis of cancer progression and metastasis. Syndecans also play important roles in interacting with growth factors, extracellular matrix and other cell surface molecules such as IGF-1 receptor. In the present review, we discuss about the syndecan structure, their role in signaling with other receptors, in addition to its general biology. The emerging roles of syndecans in the pathophysiology of human diseases, especially insulin resistance, diabetes and cancer is discussed. Abstractfeatures and their conventional roles in signaling with co-receptors. Finally, we will explore the emerging roles of syndecans in the pathophysiology of human diseases, especially type 2 diabetes. SYNDECAN STRUCTUREAll the syndecans are a type 1 transmembrane proteins that are expressed in almost every cell of the body. Four members of syndecan family have been identifi ed in mammalians such as syndecan-1, 2, 3, and 4. Syndecan-1 analogs are also identifi ed in other mammals such as mouse, rat, dog, chimpanzee, guinea pig, Chinese hamster, cat and chicken. The extracellular domains of human and mouse syndecan-1 display approximately 70% sequence homology whereas the transmembrane domain and cytoplasmic domain show 96 % and 100% sequence homology, respectively. Synthesis of four syndecan core proteins are ...

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The role of syndecans in disease and wound healing

Cited by 136 publications

References 169 publications

Transmembrane domains of the syndecan family of growth factor coreceptors display a hierarchy of homotypic and heterotypic interactions

Transmembrane domains of the syndecan family of growth factor coreceptors display a hierarchy of homotypic and heterotypic interactions

Preparation and Characterization of Laminin-Derived Peptide AG73-Coated Liposomes as a Selective Gene Delivery Tool

Syndecan as a Messenger to Link Diabetes and Cancer

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