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The cardiac syndecan-4 interactome:A role for syndecan-4 innuclear translocation of muscle LIM protein (MLP)

ABSTRACT: Biomechanical stimuli and extracellular matrix cues are important initiators for the cardiac remodeling process, and signaling hubs in the sarcolemma are important contact points between the extracellular space and cell interior, sensing and transducing biomechanical signals into a cellular response. The transmembrane proteoglycan syndecan-4 localizes to these attachment points and has been shown important in initial stages of cardiac remodeling. The objective of this study was to map the cardiac interactome of syndecan-4 to better understand its function and downstream signaling mechanisms. By combining two different affinity purification methods with mass spectrometry, we identified the cardiac syndecan-4 interactome to consist of 21 novel and 31 previously described interaction partners. 12of the novel partners were further validated to bind syndecan-4 in HEK293 (MPP7, PARVB, CCT5, CDK9, EIF22S1, PFKM, RASIP, EIF4B, PTRF/CAVIN1, AP3D1, EPB4.1 and MLP/CSRP3). 19 of the interactome partners bound differently to syndecan-4 in left ventricle lysate from aorta banded hypertrophic failing (ABHF) rats. One of these partners was the well-known mechanotransducer MLP, which showed a direct and significant increased binding to syndecan-4 in ABHF. Nuclear translocation is important in MLP mediated signalling and we found less MLP in nuclear enriched fractions from syndecan-4-/- mouse left ventricles, but an increase in nuclear MLP when syndecan-4 was overexpressed in a cardiomyocyte cell line. In the presence of a cell-permeable syndecan-4-MLP disruptor peptide, the nuclear MLP level was significantly reduced. This suggests syndecan-4 to be a mediator of nuclear translocation of MLP in the heart.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Rattus Norvegicus (rat)

TISSUE(S): Heart

SUBMITTER: Gustavo De Souza

LAB HEAD: Cathrine Carlson

PROVIDER: PXD011249 | Pride | 2019-04-09

REPOSITORIES: Pride

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Project description:We aimed to investigate the function of syndecan-1 in tumor cell adhesion and migration, with special focus on the importance of its distinct protein domains, to better understand the structure-function relationship of syndecan-1 in tumor progression. We utilized two mesenchymal tumor cell lines which were transfected to stably overexpress full-length syndecan-1 or truncated variants: the 78 which lacks the extracellular domain except the DRKE sequence proposed to be essential for oligomerization, the 77 which lacks the whole extracellular domain, and the RMKKK which serves as a nuclear localization signal. Various bioassays for cell adhesion, chemotaxis, random movement and wound healing were studied. Furthermore we performed gene microarray to analyze the global gene expression pattern influenced by syndecan-1. We found that full-length syndecan-1 enhanced cell adhesion in a dose-dependent manner. The truncated constructs only affected adhesion marginally, or not at all. Both full-length syndecan-1 and all its distinct domains inhibited serum-induced cell migration and wound closure. The full-length syndecan-1 and the 78 constructs specifically reduced cell motility/migration in random movement assay. Cell adhesion depends on the extracellular domain and also associates with the DRKE motif. Effects of syndecan-1 on migration are more complex; the pro-adhesive effect of the extracellular domain is one factor hampering migration, but the transmembrane/cytoplasmic portion seems to have additional impact. Gene microarray analysis showed that a number of genes involved in cell adhesion and migration were differentially expressed in syndecan-1 overexpressing cells. Our results demonstrate that syndecan-1 regulates mesenchymal tumor cell adhesion and migration, and different domains have differential effects. Our study provides new inputs into the better understanding of structure-function relationship of this PG in tumor progression. Gene expression profiles (Human Gene 1.0 ST) of malignant mesothelioma cells were studied in syndecan-1 overexpressing cells (N=3) and vector control cells (N=3) .

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The cardiac syndecan-4 interactome:A role for syndecan-4 innuclear translocation of muscle LIM protein (MLP)

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