Syndecan

Syndecans are a family of transmembrane heparan sulfate proteoglycans (HSPGs) involved in cell signaling, cell adhesion, and cytoskeletal organization. They are found on the surface of nearly all mammalian cells and play critical roles in development, tissue repair, inflammation, and cancer.

Syndecans consist of a core protein with an ectodomain (extracellular domain), a transmembrane domain, and a cytoplasmic domain. The ectodomain carries covalently attached heparan sulfate (HS) and chondroitin sulfate (CS) glycosaminoglycan (GAG) chains. The number and composition of these GAG chains vary depending on the syndecan type, cell type, and developmental stage.

There are four main members of the syndecan family in mammals: syndecan-1 (SDC1), syndecan-2 (SDC2), syndecan-3 (SDC3), and syndecan-4 (SDC4). Each syndecan isoform has a distinct tissue distribution and functional role, although there is also significant overlap and redundancy.

The heparan sulfate chains on syndecans mediate interactions with a wide range of extracellular ligands, including growth factors, cytokines, chemokines, extracellular matrix components (e.g., collagen, fibronectin), and enzymes. These interactions can modulate ligand activity, receptor binding, and downstream signaling pathways.

The cytoplasmic domains of syndecans interact with intracellular signaling molecules and cytoskeletal proteins, providing a link between the extracellular environment and the cell interior. These interactions influence cell shape, motility, and gene expression.

Syndecans are shed from the cell surface by proteolytic cleavage (shedding), releasing the ectodomain into the extracellular space. Shedding can be regulated by various stimuli and can modulate syndecan function by altering cell surface expression or by generating soluble ectodomains that act as signaling molecules.

Syndecan function is regulated by multiple mechanisms, including transcriptional control, post-translational modifications (e.g., phosphorylation, glycosylation), and proteolytic shedding. Dysregulation of syndecan expression or function has been implicated in various diseases, including cancer, fibrosis, and inflammation.

Syndecans are therapeutic targets for drug development. Strategies being explored include targeting syndecan expression, modulating heparan sulfate chain composition, and inhibiting syndecan shedding.