Syndecan-4: Dispensable or indispensable?

Wilcox-Adelman, Sarah A.; Denhez, Fabienne; Iwabuchi, Tokuro; Saoncella, Stefania; Calautti, Enzo; Goetinck, Paul F.

doi:10.1023/a:1025304602057

Cited by 24 publications

(22 citation statements)

References 92 publications

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“…In addition, in the absence of syndecan-4 there is a decreased ability of adapting to physiological stress situation (reviewed in Ref. 9). It is tempting to speculate that the elevated levels of GTP-bound Rac1, p38, JNK, and ATF-2 in the syndecan-4-null cells documented in the present study may be a reflection of a deregulation of signaling pathways that are normally controlled by syndecan-4 during stress situations.…”

Section: Re-expression Of Syndecan-4 In Syndecan-4-null Cells Suppresmentioning

confidence: 52%

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Syndecan-4 Regulates ATF-2 Transcriptional Activity in a Rac1-dependent Manner

Saoncella¹,

Calautti²,

Neveu

et al. 2004

Journal of Biological Chemistry

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Syndecan-4 is a transmembrane heparan sulfate proteoglycan that co-operates with integrins during cellmatrix interactions for the assembly of focal adhesions and actin stress fibers and in the phosphorylation of focal adhesion kinase (FAK) on Tyr 397 . These cellular events are regulated by the small GTPase Rho, and in the absence of syndecan-4 ligation, cellular levels of GTP-bound Rho are decreased implicating syndecan-4 in the regulation of the small GTPases. In the present study we report that, compared with wild type cells, fibronectin-adherent syndecan-4-null fibroblasts showed enhanced lamellipodia and increased Rac1 activity that could be down-regulated by re-expression of syndecan-4 in the mutant cells. Consistent with the role for Rac1 in activating p38 and JNK signaling, syndecan-4-null cells display higher levels of active p38 MAPK and JNK that were abolished by the expression of a dominant-negative RacN17 mutant. Since p38 and JNK regulate gene expression by phosphorylating and activating transcription factors, we compared both the phosphorylation state and the transcriptional activity of the ATF-2 transcription factor, as a direct p38 and JNK target in syndecan-4-null and wild type cells. In the absence of syndecan-4, both ATF-2 phosphorylation and transcriptional activity were significantly more elevated compared with wild type cells, and both activities were decreased either by the re-expression of syndecan-4 or by the expression of RacN17. Our results reveal a novel function for syndecan-4 in modulating nuclear transcriptional activity and indicate an underlying mechanism that acts at the level of Rac1-p38/JNK signaling.The syndecans make up a family of four transmembrane heparan sulfate proteoglycans that, by virtue of their heparan sulfate side chains, can bind insoluble ligands such as extracellular matrix (ECM) 1 molecules and soluble ligands such as growth factors (1). Of all the syndecans, syndecan-4 is the most ubiquitously expressed. Of the remaining family members, syndecan-1 is primarily expressed in epithelia, syndecan-2 in connective tissue, and syndecan-3 in nervous tissues. A number of studies have shown that syndecan-4 is important in adapting to physiological stresses. Its expression is up-regulated in response to hypoxia (2) and to mechanical stress (3, 4). Loss of syndecan-4 in mice results in defective renal function (5), increased mortality due to septic shock (6), and in delayed wound healing due to a reduction in cell migration and impaired angiogenesis in the granulation tissue (7). A number of studies implicate syndecan-4 in the regulation of the small GTPase Rho in events associated with cell attachment and migration. First, syndecan-4 co-operates, in a Rhomediated manner, with integrins in the assembly of focal adhesions and actin stress fibers when cells adhere to the ECM molecule fibronectin (FN) (8). Focal adhesions are macromolecular complexes that are composed of transmembrane receptors and structural and signaling cytoplasmic molecules. Integrins and syndecan-4 ar...

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Section: Re-expression Of Syndecan-4 In Syndecan-4-null Cells Suppresmentioning

confidence: 52%

“…Focal adhesions are macromolecular complexes that are composed of transmembrane receptors and structural and signaling cytoplasmic molecules. Integrins and syndecan-4 are the two transmembrane receptors of focal adhesions (9). Furthermore, syndecan-4 ligation is necessary for the phosphorylation of Tyr 397 of focal adhesion kinase (FAK).…”

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confidence: 99%

Syndecan-4 Regulates ATF-2 Transcriptional Activity in a Rac1-dependent Manner

Saoncella¹,

Calautti²,

Neveu

et al. 2004

Journal of Biological Chemistry

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“…In addition to being a coreceptor for FGF-2, syndecan-4 also has a role in cell attachment. Syndecan-4 is an essential component for the activation of focal adhesion kinase and is capable of binding fibronectin with its heparan sulfate chains (28). Consequently, the results in the migration study may be a result of the combined effects of delivering both an enhancer of FGF-2 signaling and an exogenously delivered adhesion receptor.…”

Section: Discussionmentioning

confidence: 99%

Syndecan-4 proteoliposomes enhance fibroblast growth factor-2 (FGF-2)–induced proliferation, migration, and neovascularization of ischemic muscle

Jang

Albadawi

Watkins

et al. 2012

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

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Ischemia of the myocardium and lower limbs is a common consequence of arterial disease and a major source of morbidity and mortality in modernized countries. Inducing neovascularization for the treatment of ischemia is an appealing therapeutic strategy for patients for whom traditional treatment modalities cannot be performed or are ineffective. In the past, the stimulation of blood vessel growth was pursued using direct delivery of growth factors, angiogenic gene therapy, or cellular therapy. Although therapeutic angiogenesis holds great promise for treating patients with ischemia, current methods have not found success in clinical trials. Fibroblast growth factor-2 (FGF-2) was one of the first growth factors to be tested for use in therapeutic angiogenesis. Here, we present a method for improving the biological activity of FGF-2 by codelivering the growth factor with a liposomally embedded coreceptor, syndecan-4. This technique was shown to increase FGF-2 cellular signaling, uptake, and nuclear localization in comparison with FGF-2 alone. Delivery of syndecan-4 proteoliposomes also increased endothelial proliferation, migration, and angiogenic tube formation in response to FGF-2. Using an animal model of limb ischemia, syndecan-4 proteoliposomes markedly improved the neovascularization following femoral artery ligation and recovery of perfusion of the ischemic limb. Taken together, these results support liposomal delivery of syndecan-4 as an effective means to improving the potential of using growth factors to achieve therapeutic neovascularization of ischemic tissue.

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“…Although these cells are able to form normal focal adhesions (13,27), focal adhesion formation is impaired when the cells are cultured on the cell binding fragment of fibronectin in the presence of culture medium with the heparin-binding fragment of fibronectin (27). Of interest, these syndecan-4-deficient mice develop normally, but when challenged, they exhibit impaired wound healing and decreased angiogenesis in the granulation tissue (28,29). Thus, the specific role of syndecan-4 for focal adhesion formation, especially in human cells, is uncertain and requires further study.…”

Section: Discussionmentioning

confidence: 99%

Syndecan-4 Is Required for Thrombin-induced Migration and Proliferation in Human Vascular Smooth Muscle Cells

Rauch

Millette

Kenagy

et al. 2005

Journal of Biological Chemistry

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Thrombin is a mitogen and chemoattractant for vascular smooth muscle cells (SMCs) and may contribute to vascular lesion formation. We have previously shown that human SMCs, when stimulated with thrombin, release basic fibroblast growth factor (bFGF), causing phosphorylation of FGF receptor-1 (FGFR-1). Treatment with bFGF-neutralizing antibodies (anti-bFGF) or heparin inhibits thrombin-induced DNA synthesis. We concluded that thrombin may stimulate entry into the cell cycle via bFGF release and FGFR-1 activation. In the present study, we demonstrate a requirement for not only FGFR-1 but also syndecan-4, a transmembrane heparan-sulfate proteoglycan. Inhibition of syndecan-4 expression using small interfering RNA (siRNA) resulted in reduced DNA synthesis by human SMCs after stimulation with thrombin (10 nmol/liter). Anti-bFGF antibody, which inhibits DNA synthesis in control cells, had no inhibitory effect when syndecan-4 expression was reduced by siRNA. Thrombin-or bFGF-induced SMC migration, determined in Boyden chamber assays, was reduced in cells treated with syndecan-4 or FGFR-1 siRNA or by anti-bFGF. Thrombin induced phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 in a biphasic pattern. Although thrombin-mediated ERK phosphorylation at 5 min was not affected by syndecan-4 or FGFR-1 siRNA, ERK phosphorylation at later time points was reduced. We conclude that thrombin-released bFGF binds to syndecan-4 and FGFR-1, which is required for thrombin-induced mitogenesis and migration.

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Syndecan-4: Dispensable or indispensable?

Cited by 24 publications

References 92 publications

Syndecan-4 Regulates ATF-2 Transcriptional Activity in a Rac1-dependent Manner

Syndecan-4 Regulates ATF-2 Transcriptional Activity in a Rac1-dependent Manner

Syndecan-4 proteoliposomes enhance fibroblast growth factor-2 (FGF-2)–induced proliferation, migration, and neovascularization of ischemic muscle

Syndecan-4 Is Required for Thrombin-induced Migration and Proliferation in Human Vascular Smooth Muscle Cells

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