The signaling mechanisms of syndecan heparan sulfate proteoglycans

Abstract

Summary of recent advances Syndecans are membrane proteins controlling cell proliferation, differentiation, adhesion and migration. Their extracellular domains bear versatile heparan sulphate chains that provide structural determinants for syndecans to function as co-receptors or activators for molecules like growth factors and constituents of the matrix. Syndecans also signal via their protein cores and their conserved transmembrane and cytoplasmic domains. The direct interactions and signalling cascades they support are becoming better characterized. These interactions are regulated by phosphorylation, induced clustering and shedding of the syndecan extracellular domain. Moreover evidence is emerging that syndecans concentrate in unconventional lipid domains and might govern novel vesicular trafficking pathways. Here we focus on recent findings that refine our understanding of the complex structure-function relationships of these cellular effectors.

Syntenin-mediated regulation of Sox4 proteasomal degradation modulates transcriptional output

“…Since then, it has been shown to regulate the metastatic phenotype of human melanoma cells through interactions with c-src, protein kinase C alpha and activation of nuclear factor-kB and p38 signaling pathways (Boukerche et al, , 2010Sarkar et al, 2008). Syntenin also bind and regulate syndecans as co-receptors for various growth factors and matrix components, thereby controlling cellular proliferation, differentiation, adhesion and migration (Grootjans et al, 1997;Lambaerts et al, 2009). The adapter molecule syntenin may provide crosstalk between these pathways and Sox4 that may be important for regulating the tumorigenic properties of transformed cells.…”

Metastasis Suppressor Tetraspanin CD82/KAI1 Regulates Ubiquitylation of Epidermal Growth Factor Receptor

“…This pathway is slow and involves formation of uncoated vesicles that eventually fuse with sorting endosomes. The fate of the cargo-HSPG complex is decided according to the ubiquitylation status of cargo or HSPG (e.g., syndecans) interactions (44,45) and may progress either to the lysosomal degradation or to the recycling route (44). The role of CD82 in this diversion could be in bringing EGFR in proximity to HSPG and regulating ubiquitylation on one side (discussed above) and in providing suitable lipid surroundings (e.g., gangliosides and/or cholesterol content) on the other (6).…”

A Unique Phenylalanine in the Transmembrane Domain Strengthens Homodimerization of the Syndecan-2 Transmembrane Domain and Functionally Regulates Syndecan-2

“…The extracellular domains of the syndecan family members interact with numerous matrix molecules and growth factors (10,11). For example, interactions with core protein or glycosaminoglycan, which attach to the extracellular domain, activate syndecans to regulate cell signals, leading to cytoskeletal reorganization, cell adhesion, and cell migration (9,11,12).…”