Cleavage of syndecan-4 by ADAMTS1 provokes defects in adhesion

Abstract

Syndecan-4 is a membrane-bound heparan sulfate proteoglycan that participates in cell–cell and cell–matrix interactions and modulates adhesion and migration of many cell types. Through its extracellular domain, syndecan-4 cooperates with adhesion molecules and binds matrix components relevant for cell migration. Importantly, syndecan-4 is a substrate of extracellular proteases, however the biological significance of this cleavage has not been elucidated. Here, we show that the secreted metalloprotease ADAMTS1, involved in angiogenesis and inflammatory processes, cleaves the ectodomain of syndecan-4. We further showed that this cleavage results in altered distribution of cytoskeleton components, functional loss of adhesion, and gain of migratory capacities. Using syndecan-4 null cells, we observed that ADAMTS1 proteolytic action mimics the outcome of genetic deletion of this proteoglycan with regards to focal adhesion. Our findings suggest that the shedding of syndecan-4 by ADAMTS1 disrupts cell adhesion and promotes cell migration.

Innate immune signaling induces expression and shedding of the heparan sulfate proteoglycan syndecan‐4 in cardiac fibroblasts and myocytes, affecting inflammation in the pressure‐overloaded heart

“…In Paper II, we observed a parallel upregulation of syndecan-4 and three sheddases proposed to regulate its shedding, 193,195 i.e. ADAMTS1, ADAMTS4 and MMP9.…”

“…193 In fact, this sheddase was found to cleave syndecan-4 close to the first HS chain attachment site. Interestingly, the juxtamembrane domain was shown to be essential for both constitutive and accelerated shedding of syndecan-1, as mutations in the amino acid sequence in this site blocked shedding both in vitro and in vivo.…”

“…198 In line with this, ADAMTS1-induced shedding of syndecan-4 was shown to reduce focal adhesions and promote migration of fibroblasts, thus resembling the phenotype of syndecan-4-deficient cells. 193 The small leucine-rich proteoglycan lumican in heart failure: a novel regulator of fibrotic signaling?…”

The ADAMTS1 Protease Gene Is Required for Mammary Tumor Growth and Metastasis

“…1,2 Mice with Adamts1-null mutation exhibit urogenital defects and female infertility because of impaired remodeling of ovarian extracellular matrix (ECM), but ovarian steroid production and lactation are normal. [3][4][5] A range of ECM proteins have been identified as potential ADAMTS1 substrates, including collagens, 6 nidogen, 7 and syndecan-4 8 ; however, the proteoglycans versican and aggrecan have been consistently shown to be key ADAMTS1 targets. 4,9,10 ADAMTS1 processing of versican is important in cell migration during wound healing, 11 endothelial cell invasion, 12 and remodeling of cardiac jelly ECM during heart morphogenesis.…”

Shedding; towards a new paradigm of syndecan function in cancer

“…After co-transfecting 293T cells with ADAMTS1 and an N-terminally HAtagged full-length syndecan-4 construct, a soluble fragment (approximately 6-7 kDa) of HA-tagged syndecan-4 extracellular domain was detected in conditioned media (35). This shedding of syndecan-4 was reduced by BB-94, a metalloprotease inhibitor that partially inhibits the protease activity of ADAMTS1 (35).…”