Control of morphology, cytoskeleton and migration by syndecan-4

Longley, Robert L.; Woods, Anne; Fleetwood, Allison; Cowling, Graham; Gallagher, John T.; Couchman, John R.

doi:10.1242/jcs.112.20.3421

Cited by 172 publications

(18 citation statements)

References 51 publications

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“…In fibronectin, the RGD sequence is located in a short loop that extends from the tenth type III repeat (FNIII10) where it mediates adhesion for a variety of cell types, including epithelial cells, endothelial cells and fibroblasts, via β 1 and β 3 integrins (23,24). Ligation of cell surface integrins with the RGD sequence of fibronectin triggers a cascade of cell signaling events, including protein kinase C activation and Rho-mediated actomyosin contractility, that lead to changes in cell shape (25), focal adhesion composition (26,27), and extracellular matrix assembly (28). Critically, activation of components of these adhesion-based signaling cascades has been associated with reduced endothelial and epithelial barrier function and increased prevalence of inflammatory diseases (29).…”

Section: Introductionmentioning

confidence: 99%

Receptor binding domain of SARS-CoV-2 is a functional αv-integrin agonist

Norris

Pan

Hocking

2022

Preprint

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Among the novel mutations distinguishing SARS-CoV-2 from similar respiratory coronaviruses is a K403R substitution in the receptor-binding domain (RBD) of the viral spike (S) protein within its S1 region. This amino acid substitution occurs near the angiotensin-converting enzyme 2 (ACE2)-binding interface and gives rise to a canonical RGD adhesion motif that is often found in native extracellular matrix proteins, including fibronectin. In the present study, the ability of recombinant S1-RBD to bind to cell surface integrins and trigger downstream signaling pathways was assessed and compared to RGD-containing, integrin-binding fragments of fibronectin. S1-RBD supported adhesion of both fibronectin-null mouse embryonic fibroblasts as well as primary human small airway epithelial cells. Cell adhesion to S1-RBD was cation- and RGD-dependent, and was inhibited by blocking antibodies against αv and β3, but not α5 or β1, integrins. Similarly, direct binding of S1-RBD to recombinant human αvβ3 and αvβ6 integrins, but not α5β1 integrins, was observed by surface plasmon resonance. Adhesion to S1-RBD initiated cell spreading, focal adhesion formation, and actin stress fiber organization to a similar extent as fibronectin. Moreover, S1-RBD stimulated tyrosine phosphorylation of the adhesion mediators FAK, Src, and paxillin, Akt activation, and supported cell proliferation. Together, these data demonstrate that the RGD sequence within S1-RBD can function as an αv-selective integrin agonist. This study provides evidence that cell surface αv-containing integrins can respond functionally to spike protein and raise the possibility that S1-mediated dysregulation of ECM dynamics may contribute to the pathogenesis and/or post-acute sequelae of SARS-CoV-2 infection.

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Section: Introductionmentioning

confidence: 99%

Receptor binding domain of SARS-CoV-2 is a functional αv-integrin agonist

Norris

Pan

Hocking

2022

Preprint

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“…Distinct studies have already reported a significance of syndecans expression in normal cell functioning and also in alterations linked with different diseases, including cancers . Syndecan-1 (SDC1) is largely expressed in mesenchymal and epithelial cells, syndecan-2 is predominant in mesenchymal, neuronal, and epithelial cells, syndecan-3 is almost exclusively characteristic for neuronal and musculoskeletal tissues, while syndecan-4 (SDC4) is common for a wide variety of cell types. , SDC1 shows the highest expression on epithelial cells such as keratinocytes and terminally differentiated cells such as plasma cells. − It plays an important role in regulation of inflammation (as suggested by increased leukocyte–endothelial interactions in knockout mice) or in chemokine gradient formation for trans-endothelial and trans-epithelial migrations of neutrophils. , SDC4 is mainly associated with cellular adhesion and migration. , It occurs alongside integrins within the focal adhesions to which ECM proteins bind. , In syndecan-4-deficient mice, an absence of SDC4 causes low prevention of mice to endotoxin shock and impairments in wound healing . Syndecans facilitate interactions of integrins with ECM. − SDC4 is frequently associated with β 1 and β 3 integrins in focal adhesions. − SDC1 interacts with α v β 3 integrin associated with vitronectin and also with α v β 5 integrin that binds to matrix macromolecules and proteinases and thereby stimulates angiogenesis …”

mentioning

confidence: 99%

“…11,12 SDC4 is mainly associated with cellular adhesion and migration. 13,14 It occurs alongside integrins within the focal adhesions to which ECM proteins bind. 15,16 In syndecan-4-deficient mice, an absence of SDC4 causes low prevention of mice to endotoxin shock 17 and impairments in wound healing.…”

mentioning

confidence: 99%

Unbinding Kinetics of Syndecans by Single-Molecule Force Spectroscopy

Herman

Lekka

Ptak

2018

J. Phys. Chem. Lett.

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Syndecans are transmembrane proteoglycans that, together with integrins, control cell interactions with extracellular matrix components. Despite structural similarities between all members of the syndecan family, their specific attachment to extracellular matrix proteins is defined by heparan and chondroitin chains. We postulate various unbinding kinetics for each type of single syndecan complex. Force spectroscopy data, recorded by atomic force microscope, were analyzed using two theoretical approaches describing force-induced unbinding, authored by Bell-Evans and Dudko-Hummer-Szabo. Our results reveal distinct unbinding pathways dependent on the syndecan family member. Syndecan-1 unbinds by passing over two energy barriers, inner and outer. Syndecan-4 unbinds by crossing over only one energy barrier. It has already been reported that both syndecans bear heparan chains that are structurally indistinguishable. Our finding reveals that unbinding of single syndecan complexes is family-member-dependent. Distinct unbinding pathways can be attributed to structural differences of heparan and chondroitin chains.

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“…For example, wound healing is delayed in syndecan 1-null mice (Stepp et al, 2002), and over-expressing syndecan 1 in mice also leads to delayed wound healing with defective granulation tissue angiogenesis (Elenius et al, 2004). Similar observations have also been made for syndecan 4 in wound closure (Longley et al, 1999;Echtermeyer et al, 2001) and myocardial infarction (Matsui et al, 2011). Further work is therefore required to determine the effects of manipulating syndecan expression in disease.…”

Section: (Iv) Roles Of Syndecans In Osteogenesismentioning

confidence: 68%

216 Regulation of Vascular Calcification by Syndecan 4

Borland

Merry

Canfield

2015

Heart

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Vascular calcification is the formation of bone and cartilage within blood vessels. It involves the osteogenic differentiation of vascular smooth muscle cells (VSMCs), VSMC apoptosis, calcifying matrix vesicle release and extracellular matrix mineralisation. This disease process has the potential to be regulated by proteoglycans (PGs), which comprise a protein core and glycosaminoglycan (GAG) chains. Syndecan 4 is a transmembrane PG, which has been previously implicated in the regulation of growth factor signalling and apoptosis, both of which play an important role in vascular calcification. This study tests the hypothesis that GAGs, and syndecan 4 specifically, regulate vascular calcification.VSMCs were cultured with 3 mM β-glycerophosphate (β-GP) to induce mineralisation. Controls were cultured without β-GP. Osteogenic differentiation was confirmed by the up-regulation of Runx2, Msx2 and BMP-2, and down-regulation of αSMA and SM22α mRNA. During VSMC osteogenic differentiation and mineralisation, the mRNA levels of specific enzymes involved in the biosynthesis of heparan sulphate (HS) (including NDST1, P < 0.001) and chondroitin/dermatan sulphate (CS/DS) (including C4ST1 and DSEL, both P < 0.001) were up-regulated in β-GP-treated VSMCs compared to controls. To correlate the glycomic transcription profile of mineralising VSMCs with the GAGs synthesised by these cells, 3H-GAGs were isolated from confluent and mineralising VSMCs and characterised using specific scission agents. The ratio of DS to CS, and CS/DS 4-O-sulphation was increased in mineralising VSMCs. VSMC mineralisation was also associated with shortening of HS chains (˜50% decrease).Syndecan 4 displays HS and/or CS/DS chains. The mRNA expression levels of syndecan 4 were significantly increased (˜5-fold; P < 0.001) in β-GP-treated VSMCs at the late stages of mineralisation. Knocking-down syndecan 4 expression using two different siRNAs significantly increased VSMC mineralisation in the presence of β-GP (˜2-fold; P < 0.01). Syndecan 4 regulates FGF-2 signalling, and interestingly, FGF-2 mRNA was also increased (˜19-fold; P < 0.001) in β-GP-treated VSMCs at the late stages of mineralisation. In response to exogenous FGF-2 (50 ng/ml), Akt activation was reduced in syndecan 4 siRNA VSMCs when compared to controls. FGF-2 inhibits VSMC mineralisation, and this ability was partially lost in the absence of syndecan 4.Together, these studies demonstrate that VSMC mineralisation is associated with changes in CS/DS chain composition. We also demonstrate for the first time that syndecan 4 plays a role in VSMC mineralisation. Studies are now underway to characterise syndecan 4 expression in human calcified aortic sections.

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Control of morphology, cytoskeleton and migration by syndecan-4

Cited by 172 publications

References 51 publications

Receptor binding domain of SARS-CoV-2 is a functional αv-integrin agonist

Receptor binding domain of SARS-CoV-2 is a functional αv-integrin agonist

Unbinding Kinetics of Syndecans by Single-Molecule Force Spectroscopy

216 Regulation of Vascular Calcification by Syndecan 4

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