Syndecan-4, or SDC4, is a molecule found on the surface of cells throughout the body. It belongs to the syndecan family of proteins, which are involved in various cellular processes. SDC4 acts as a receptor, helping cells interact with their surroundings and respond to signals.
Structure and Location
SDC4 is classified as a type I transmembrane proteoglycan, meaning it spans the cell membrane and has sugar chains attached. It consists of three main parts: an extracellular domain, a transmembrane domain, and a cytoplasmic tail. The extracellular domain extends outside the cell and is adorned with heparan sulfate chains. These chains interact with various molecules outside the cell.
The transmembrane domain anchors SDC4 within the cell membrane, while the short cytoplasmic tail extends into the cell’s interior. This cytoplasmic tail interacts with various signaling and structural proteins inside the cell, linking the outside environment to internal cellular machinery. SDC4 is present on the surface of most mammalian cell types, including fibroblasts and epithelial cells.
Key Functions
SDC4 plays a multifaceted role in cellular processes, bridging the cell’s interior and external environment. A primary role is in cell adhesion, enabling cells to stick to each other and to the extracellular matrix, the network of molecules surrounding cells. It binds to extracellular matrix components like fibronectin, which aids in forming focal adhesions—specialized structures where cells connect to their environment.
SDC4 is also involved in cell migration, the directed movement of cells, a process in development, wound healing, and immune responses. It influences cell movement by regulating small GTPases like Rac1 and affecting the actin cytoskeleton, the cell’s internal scaffolding. SDC4 also functions as a co-receptor for various growth factors, such as fibroblast growth factor-2 (FGF2), hepatocyte growth factor (HGF), and vascular endothelial growth factor (VEGF). By binding to these growth factors, SDC4 helps present them to their specific receptors, amplifying growth signals that promote cell growth and repair.
The cytoplasmic tail of SDC4 interacts with intracellular signaling molecules, including protein kinase C-alpha (PKCα) and focal adhesion kinase (FAK). This interaction helps organize the cell’s internal structure and coordinate responses to external cues. For instance, SDC4 can activate PKCα in the presence of phosphatidylinositol 4,5-bisphosphate (PIP2), regulating various signaling pathways. SDC4’s ability to link the extracellular matrix to the actin cytoskeleton coordinates cell shape, movement, and responsiveness.
SDC4 in Health and Disease
SDC4’s diverse functions have implications for health, participating in normal physiological processes and contributing to disease. In healthy individuals, SDC4 is involved in tissue repair and wound healing, with expression increasing after injury. It contributes to extracellular matrix protein deposition and immune cell accumulation at wound sites. For instance, studies in zebrafish heart regeneration show SDC4 is necessary for early repair responses, influencing matrix deposition, immune cell accumulation, and cell proliferation.
SDC4 also has dual roles in disease. In cancer, SDC4 expression can be dysregulated, either overexpressed or downregulated depending on the cancer type. High expression is observed in several cancers, including estrogen receptor-negative breast cancer, glioma, liver cancer, melanoma, osteosarcoma, and bladder cancer, often serving as an unfavorable biomarker. SDC4 can influence tumor progression by regulating cell proliferation, migration, and angiogenesis.
SDC4 is also implicated in inflammatory responses and fibrosis, which is the excessive scarring of tissues. In heart disease, SDC4 expression can be elevated in patients with acute myocardial infarction. Increased shedding of SDC4 from cardiac cells can generate soluble pro-inflammatory molecules, activating immune cell recruitment and contributing to immune responses. Research suggests that reducing SDC4 levels could have anti-hypertrophic, anti-fibrotic, and anti-inflammatory effects in the heart.