Functional Role of Syndecan-1 Cytoplasmic V Region in Lamellipodial Spreading, Actin Bundling, and Cell Migration

Chakravarti, Ritu; Sapountzi, Vasileia; Adams, Josephine C.

doi:10.1091/mbc.e04-10-0907

Cited by 47 publications

(41 citation statements)

References 60 publications

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“…Clustering of another syndecan family member, syndecan-1, also results in the enhanced cell spreading and formation of lamellipodia but is independent of PDZ-binding domain interactions. 43 In summary, our results suggest that in endothelial cells, S4 forms a complex with a PDZ partner, synectin, that inhibits Rac1 activation. Clustering of S4 locally releases this inhibition, resulting in targeting of the active Rac1 to the leading edge of the cell, thus promoting cell motility.…”

Section: Discussionmentioning

confidence: 66%

Syndecan-4 Clustering Induces Cell Migration in a PDZ-Dependent Manner

Tkachenko¹,

Elfenbein²,

Tı̂rziu³

et al. 2006

Circulation Research

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Abstract-Cell migration is a dynamic process involving formation of a leading edge in the direction of migration and adhesion points from which tension is generated to move the cell body forward. At the same time, disassembly of adhesion points occurs at the back of the cell, a region known as the trailing edge. Syndecan-4 (S4) is a transmembrane proteoglycan thought to be involved in the formation of focal adhesions. Recent studies have shown that its cytoplasmic domain can engage in signal transduction, making S4 a bona fide receptor. Here, we show that ligand clustering of cell surface S4 on endothelial cells initiates a signaling cascade that results in activation of Rac1, induction of cell polarization, and stimulation of cell migration that depends on S4 interaction with its PDZ-binding partner. Expression of an S4 mutant lacking its PDZ-binding region (S4-PDZ Ϫ ) leads to decreased cell motility and a failure to form a trailing edge. On clustering S4, but not S4-PDZ Ϫ , targets activated Rac1 to the leading edge of live cells. Cells lacking synectin, a PDZ domain containing protein that interacts with S4, fail to migrate in response to S4 clustering. Both S4-PDZ Ϫ -expressing and synectin Ϫ/Ϫ endothelial cells exhibit elevated basal levels of Rac1. Thus, our data suggest that S4 promotes endothelial cell migration in response to ligand binding by activating Rac1 and localizing it to the leading edge, and that these processes are dependent on its PDZ-binding domain interaction with synectin. (Circ Res. 2006;98:1398-1404.)Key Words: syndecan Ⅲ synectin Ⅲ migration Ⅲ endothelial cells Ⅲ Rac1 Ⅲ PDZ S yndecans are a family of four transmembrane proteoglycans containing both heparan sulfate and chondroitin sulfate chains. Different family members are expressed in various cell types, with syndecan-4 (S4) demonstrating nearly ubiquitous expression. Syndecans have been thought to act as coreceptors for various heparin-binding growth factors such as fibroblast growth factors (FGFs), vascular endothelial growth factors, and fibronectin-binding integrins. [1][2][3][4] However, recent studies have suggested that the intracellular domains of syndecans, and in particular, the S4 intracellular domain, can directly engage in signal transduction. [5][6][7][8][9] The cytoplasmic tail of the syndecans contains two highly conserved domains. The first (C1) is the membrane-proximal region that binds tubulin, Src kinase, ezrin, and cortactin. 3 The second (C2) is a C-terminal region that contains a PDZ-domain binding motif. The part of the molecule between the two conserved domains has been termed the variable domain, and its sequence is unique to each syndecan family member. The variable domain of S4 binds to the phosphatidyl inositol 4,5,bisphosphate/protein kinase C␣ (PKC␣) complex, ␣-actinin, and syndesmos. 3 These interactions are responsible for the previously demonstrated S4 role in cytoskeleton regulation that includes formation of focal adhesions, of dynamic stress fibers, and of cell protrusions. 9 -15 S4 is an acut...

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Section: Discussionmentioning

confidence: 66%

Syndecan-4 Clustering Induces Cell Migration in a PDZ-Dependent Manner

Tkachenko¹,

Elfenbein²,

Tı̂rziu³

et al. 2006

Circulation Research

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“…RGD, a fragment of fibronectin, interacts with select integrin cellsurface receptors that, when upregulated, promote migration and proliferation. 26 AG73, a fragment of laminin-1, interacts with the heparin sulfate domain of syndecan-1 27 that is found at the leading edge of wounds, 28 and the lack of syndecan-1 activation results in a decreased migration rate. 29 The tight regulation of both integrins and syndecans in the native cellular environment during wound healing provides sufficient motivation to use RGD and AG73 as the initial chemical cues in the hydrogel arrays described here.…”

Section: Resultsmentioning

confidence: 99%

Arrays of topographically and peptide-functionalized hydrogels for analysis of biomimetic extracellular matrix properties

Wilson

Jiang

Yáñez-Soto

et al. 2012

Journal of Vacuum Science &Amp; Technology B, Nanotechnology and Microelectronics: Materials, Processing, Measurement, and Phen

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Epithelial cells reside on specialized extracellular matrices that provide instructive cues to regulate and support cell function. The authors have previously demonstrated that substrate topography with dimensions similar to the native extracellular matrix (submicrometer and nanoscale features) significantly impacts corneal epithelial proliferation and migration. In this work, synthetic hydrogels were modified with both topographic and biochemical cues, where specified peptide ligands were immobilized within nanopatterned hydrogels. The efficient, systematic study of multiple instructive cues (peptide, peptide concentration, topographic dimensions), however, is contingent on the development of higher throughput platforms. Toward this goal, the authors developed a hydrogel array platform to systematically and rapidly evaluate combinations of two different peptide motifs and a range of nanoscale topographic dimensions. Specifically, distinct functional pegylated peptide ligands, RGD (GGGRGDSP) and AG73 (GRKRLQVQLSIRT), were synthesized for incorporation into an inert hydrogel network. Elastomeric stencils with arrays of millimeter-scale regions were used to spatially confine hydrogel precursor solutions on elastomeric stamps with nanoscale patterns generated by soft lithography. The resulting topographically and peptide-functionalized hydrogel arrays were used to characterize single cell migration. Epithelial cell migration speed and persistence were governed by both the biochemical and topographical cues of the underlying substrate.

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“…In addition, the Sdc1 cytoplasmic domain has been shown to mediate cell spreading and migration (Chakravarti et al, 2005). whereas Sdc4 has been shown to interact with integrins at focal adhesions during wound healing (Alexopoulou et al, 2007), less is known about how Sdc1 mediates migration.…”

Section: Introductionmentioning

confidence: 99%

Reduced migration, altered matrix and enhanced TGFβ1 signaling are signatures of mouse keratinocytes lacking Sdc1

Stepp

Liu

Pal‐Ghosh

et al. 2007

Journal of Cell Science

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We have reported previously that syndecan-1 (Sdc1)-null mice show delayed re-epithelialization after skin and corneal wounding. Here, we show that primary keratinocytes obtained from Sdc1-null mice and grown for 3-5 days in culture are more proliferative, more adherent and migrate more slowly than wt keratinocytes. However, the migration rates of Sdc1-null keratinocytes can be restored to wild-type levels by replating Sdc1-null keratinocytes onto tissue culture plates coated with fibronectin and collagen I, laminin (LN)-332 or onto the matrices produced by wild-type cells. Migration rates can also be restored by treating Sdc1-null keratinocytes with antibodies that block α6 or αv integrin function, or with TGFβ1. Antagonizing either β1 integrin function using a function-blocking antibody or TGFβ1 using a neutralizing antibody reduced wild-type keratinocyte migration more than Sdc1-null keratinocyte migration. Cultures of Sdc1-null keratinocytes accumulated less collagen than wild-type cultures but their matrices contained the same amount of LN-332. The Sdc1-null keratinocytes expressed similar total amounts of eight different integrin subunits but showed increased surface expression of αvβ6, αvβ8, and α6β4 integrins compared with wild-type keratinocytes. Whereas wild-type keratinocytes increased their surface expression of α2β1, αvβ6, αvβ8, and α6β4 after treatment with TGFβ1, Sdc1-null keratinocytes did not. Additional data from a dual-reporter assay and quantification of phosphorylated Smad2 show that TGFβ1 signaling is constitutively elevated in Sdc1-null keratinocytes. Thus, our results identify TGFβ1 signaling and Sdc1 expression as important factors regulating integrin surface expression, activity and migration in keratinocyte and provide new insight into the functions regulated by Sdc1.

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Functional Role of Syndecan-1 Cytoplasmic V Region in Lamellipodial Spreading, Actin Bundling, and Cell Migration

Cited by 47 publications

References 60 publications

Syndecan-4 Clustering Induces Cell Migration in a PDZ-Dependent Manner

Syndecan-4 Clustering Induces Cell Migration in a PDZ-Dependent Manner

Arrays of topographically and peptide-functionalized hydrogels for analysis of biomimetic extracellular matrix properties

Reduced migration, altered matrix and enhanced TGFβ1 signaling are signatures of mouse keratinocytes lacking Sdc1

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