Syndecans are a class of single-pass transmembrane proteoglycans widely present on the surface of mammalian cells, and having significant biological functions. These proteins play a critical role in extracellular matrix (ECM) interactions, signal transduction, and regulation of cell behavior.
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Structure of Syndecans
Syndecans are proteoglycans composed of a core protein and at least one covalently attached glycosaminoglycan (GAG) chain, exhibiting high structural diversity. In mammals, four genes encoding syndecan core proteins have been identified, namely syndecan-1 through syndecan-4. Their structure can be divided into three main domains: the extracellular domain (ED), transmembrane domain (TMD), and cytoplasmic domain (CD).
Fig. 1 Domain organization of human syndecans with proteolytic cleavage sites (Gondelaud F., Ricard‐Blum S. 2019).
The extracellular domain of syndecans is typically released into the extracellular environment through limited proteolysis, containing cleavage sites that interact with matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinase domain proteins (ADAMs). This structural feature enables syndecans to play crucial roles in extracellular matrix remodeling and regulation of signaling molecules. syndecan-1's extracellular domain inhibits osteoclast differentiation by binding to specific receptors, whereas syndecan-4's extracellular domain promotes tubulointerstitial fibrosis.
The transmembrane domain of syndecans regulates their role in intracellular signaling. This domain drives self-association through a conserved GXXXG motif and forms asymmetric α-helical dimers in micelles, a crucial structural feature for understanding their role in cell signaling. Syndecan-4's transmembrane domain plays a significant role in modulating cellular signaling pathways.
Syndecans' cytoplasmic domain consists of two conserved regions, C1 and C2, and a variable region V. The V region contains conserved amino acid residues that facilitate syndecans' specific signaling. Syndecan-4's cytoplasmic domain forms a symmetric clamp-like structure, which undergoes conformational changes upon binding to syndentin-1 and phosphatidylinositol 4,5-bisphosphate, thereby regulating intracellular signaling pathways.
Biological Functions of Syndecans
Syndecans play crucial roles in various biological processes, primarily functioning as receptors and co-receptors and regulating cell behavior and signaling. Syndecans also control cytoplasmic calcium balance and cellular behavior by regulating transient receptor potential channels (TRPCs). Moreover, they are pivotal in lipid metabolism, tissue regeneration, and angiogenesis, and participate in the pathogenesis of several diseases.
As Receptors and Co-receptors
Syndecans interact with various signaling molecules such as growth factors, cytokines, and extracellular matrix proteins via their GAG chains, regulating cell proliferation, differentiation, and migration. For instance, syndecan-4 plays a crucial role in integrin-mediated signaling, modulating cell adhesion and migration.
Regulation of Cell Behavior and Signaling
Syndecans regulate cellular behavior and signaling by controlling cytoplasmic calcium balance through modulation of transient receptor potential channels (TRPCs). Syndecan-1, for example, interacts with EGFR in breast cancer cells, promoting tumor cell proliferation and migration.
Role in Lipid Metabolism and Tissue Regeneration
Syndecans are vital in lipid metabolism and tissue regeneration processes. Syndecan-1, through interactions with lipid transport proteins, regulates lipid metabolism and plays a critical role in liver regeneration.
Involvement in Angiogenesis and Fibrosis
Syndecan-4 plays a significant regulatory role in angiogenesis and fibrosis processes by influencing endothelial cell behavior to promote new blood vessel formation. Additionally, in renal fibrosis, syndecan-4 facilitates fibrosis progression by regulating fibroblast activation.
Syndecans Interaction Network
Researchers have constructed the first comprehensive interaction network of syndecans through literature compilation, database queries, and large-scale high-throughput mass spectrometry data. This network reveals syndecans' importance in cellular communication and signaling.
Consensus Interaction Network
The four syndecans share 18 binding proteins, including themselves, capable of forming homotypic and heterotypic dimers. Proteins in this network are primarily involved in cytoskeletal organization and signaling, such as peripheral membrane protein CASK, tyrosine-protein kinase Fyn, and proto-oncogene tyrosine-protein kinase Src.
Specific Interaction Networks
Each syndecan has specific interaction proteins crucial for its functional roles. For instance, syndecan-1's specific interactors are mainly membrane and extracellular proteins involved in cell communication and signaling; syndecan-2's interactors are 25% associated with lysosomes; syndecan-3's interactors are 75% extracellular proteins; syndecan-4's interactors are 39% related to exosomes, critical in intercellular communication and cancer development.
Formation of Ternary Complexes
Syndecans can also form ternary complexes enhancing their regulatory roles in cellular functions. For example, syndecan-1's extracellular domain forms complexes with α3β1 integrin and HER2, regulating tumor cell signaling. Syndecan-4's extracellular domain forms complexes with α3β1 integrin and EGFR, modulating cell migration and adhesion.
Syndecans in Disease
Syndecans play crucial roles in the pathogenesis of various diseases, where their dysregulated expression or function is closely associated with disease onset and progression.
Cancer
Syndecans exhibit abnormal expression in various cancers, influencing tumor cell proliferation, migration, and invasion. For instance, syndecan-1 is upregulated in breast and lung cancers, promoting the malignant behavior of tumor cells; syndecan-4 in colon cancer regulates cell migration and adhesion, facilitating cancer cell invasion and metastasis.
Cardiovascular Diseases
Syndecans are also pivotal in cardiovascular diseases. Syndecan-4 contributes to cardiac fibrosis and pathological remodeling post-myocardial infarction by regulating fibroblast activation. Syndecan-1 interacts with inflammatory cells in atherosclerosis, modulating vascular inflammation responses.
Inflammation and Immune Diseases
Syndecans play critical regulatory roles in inflammation and immune diseases. Syndecan-1's dysregulation is associated with inflammatory bowel disease and rheumatoid arthritis, influencing inflammation cell activation and migration, and contributing to disease pathogenesis. Syndecan-4 affects airway remodeling and inflammation responses in asthma and chronic obstructive pulmonary disease by modulating airway smooth muscle cell functions.
Infection and Host-Pathogen Interactions
Syndecans are also crucial in host-pathogen interactions. For instance, syndecan-1 acts as a receptor for pathogens in bacterial and viral infections, regulating pathogen entry and dissemination. Syndecan-4 influences host immune responses and disease progression in parasitic infections by modulating immune cell functions.
Conclusion
Syndecans, as a significant class of single-pass transmembrane protein glycoproteins, play pivotal roles in cellular communication and signaling. Their complex structural features and extensive interaction networks place them at the forefront of numerous biological processes, particularly in disease onset and progression. Further exploration of syndecans' structure, biological functions, and interaction networks will unveil their regulatory mechanisms in cellular functions, potentially offering novel insights and targets for diagnosing and treating various diseases.
Research into syndecans not only enhances our understanding of the intricate mechanisms behind cell behavior and signaling but also provides a valuable knowledge base for future medical research and clinical applications. Continued investigation in this field will further illuminate the importance of syndecans in health and disease, paving the way for breakthroughs and advancements in biomedical sciences.
References
- Gondelaud F., Ricard‐Blum S. Structures and interactions of syndecans. The FEBS Journal. 2019, 286 (15): 2994-3007.
- Rapraeger A. C. Syndecan-regulated receptor signaling. The Journal of Cell Biology. 2000, 149 (5): 995-8.
- Bertrand J., Bollmann M. Soluble syndecans: biomarkers for diseases and therapeutic options. British Journal of Pharmacology. 2019, 176 (1): 67-81.
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