Syndecan
Encyclopedia
Syndecans are single transmembrane domain proteins that are thought to act as coreceptors, especially for G protein-coupled receptor
s. These core proteins carry three to five heparan sulfate
and chondroitin sulfate
chains, which allow for interaction with a large variety of ligands including fibroblast growth factor
s, vascular endothelial growth factor
, transforming growth factor
-beta, fibronectin
and antithrombin
-1. Interactions between fibronectin and some syndecans can be modulated by the extracellular matrix
protein tenascin
-C.
duplication and divergent evolution from a single ancestral gene.
The syndecan numbers reflect the order in which the cDNAs for each family member were cloned. All syndecans have an N-terminal signal peptide
, an ectodomain
, a single hydrophobic transmembrane domain, and a short C-terminal cytoplasmic domain..All syndecans are anchored to plasma membrane via a 24-25 amino acid long hydrophobic transmembrane domain, in contrast to another type of cell surface proteoglycans that attaches to cell membrane using a glycosyl-phosphatidyl-inositol linkage .The most obvious differences between syndecans include
(together with differences in distribution) the subclassification
of the family depending on the existence of GAG binding
sites either at both ends of the ectodomain (syndecan-1 and -
3) or at the distal part only (syndecan-2 and -4) and a relatively
long Thr-Ser-Pro-rich area in the middle of syndecan-
3’s ectodomain .The ectodomains show the least amount of amino acid
sequence conservation
, not more than 10–20%; in contrast, the transmembrane and cytoplasmic domains share approximately 60–70% amino acid sequence identity.
The transmembrane domains contain an unusual alanine/glycine sequence motif
, while the cytoplasmic domain is essentially composed of two regions of conserved amino acid sequence
(C1 and C2), separated by a central variable sequence of amino acids that is distinct for each family member (V).
In mammalian cells, syndecans are expressed by unique genes located on different chromosomes. This is general lack of evidence of alternate splicing in syndecan genes. All members of the syndecan family have 5 exons. The difference in size of the syndecans is credited to the variable length of exon 3, which encodes a spacer domain [1, 14]. In humans, the amino acid length of syndecan 1, 2, 3 and 4 is 310, 201, 346 and 198 respectively. Glycosaminoglycan chains, a member of the heparan sulfate group, are an important component of syndecan and are responsible for a diverse set of syndecan functions. The addition of glycosaminoglycans to syndecan is controlled by a series of post- translation events. The preferential site for the addition of glycosaminoglycans is on a serine residue followed by glycine residue, where the linker is attached for the elongation of the glycosaminoglycans by α-N-acetylglucosaminyltransferase I [1]. The linker is composed of four saccharides, first one being xylose, which is an unusual sugar in a unique place, attached to serine of the protein core and sequentially followed by two galactose and a β-D-glucuronic acid [1, 12].
proteins for cell–cell adhesion [1, 2, 12]. A final role is in tumor suppression and progression. Syndecans act as tumor inhibitors by preventing cellular proliferation of tumor cell lines. For example, in the epithelial-derived tumor-cell line, S115, the syndecan 1 ectodomain suppresses the growth of S115 cells without affecting the growth of normal epithelial cells [7]. However, syndecan 1 expression also has a role in tumor progression in myeloma and other cancers [5, 6, 9, 15].
and inhibition of syndecan 4 reduces cartilage destruction in mouse models of OA.
. High levels of shed syndecan1 in a patient's serum typically is correlated with poor prognosis.
Syndecan 1 is the most studied of all the syndecans in cancer research. Many studies have shown that syndecan 1 plays an important role in cancer progression, and also can be used as cancer biomarker. For example, syndecan 1 expression is higher in the bone marrow of the patients suffering from the multiple myeloma [9]. In one published study, the cells expressing the soluble syndecan 1 ectodomain promoted the growth and metastasis of B-lymphoid tumors more extensively than cells bearing surface syndecan 1 or lacking syndecan 1 expression [16]. Similarly, syndecan 1 expression has been linked with low differentiation in squamous cell carcinoma of the head and neck [15]. Syndecan 1 also has been linked with cancer progression by mediating the effects of growth factors in the cells. For example, syndecan 1 expression is increased in ductal breast carcinomas and is associated with factors of angiogenesis and lymphangiogenesis [5]. Studies from patients suffering from endometrial cancer have shown that these patients have increased syndecan 1 expression, and also that expression of this protein positively regulates the endometrial hyperplasia that can progress to endometrial cancer [6].
G protein-coupled receptor
G protein-coupled receptors , also known as seven-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptor, and G protein-linked receptors , comprise a large protein family of transmembrane receptors that sense molecules outside the cell and activate inside signal...
s. These core proteins carry three to five heparan sulfate
Heparan sulfate
Heparan sulfate is a linear polysaccharide found in all animal tissues. It occurs as a proteoglycan in which two or three HS chains are attached in close proximity to cell surface or extracellular matrix proteins...
and chondroitin sulfate
Chondroitin sulfate
Chondroitin sulfate is a sulfated glycosaminoglycan composed of a chain of alternating sugars . It is usually found attached to proteins as part of a proteoglycan. A chondroitin chain can have over 100 individual sugars, each of which can be sulfated in variable positions and quantities...
chains, which allow for interaction with a large variety of ligands including fibroblast growth factor
Fibroblast growth factor
Fibroblast growth factors, or FGFs, are a family of growth factors involved in angiogenesis, wound healing, and embryonic development. The FGFs are heparin-binding proteins and interactions with cell-surface associated heparan sulfate proteoglycans have been shown to be essential for FGF signal...
s, vascular endothelial growth factor
Vascular endothelial growth factor
Vascular endothelial growth factor is a signal protein produced by cells that stimulates vasculogenesis and angiogenesis. It is part of the system that restores the oxygen supply to tissues when blood circulation is inadequate....
, transforming growth factor
Transforming growth factor
Transforming growth factor is used to describe two classes of polypeptide growth factors, TGFα and TGFβ....
-beta, fibronectin
Fibronectin
Fibronectin is a high-molecular weight glycoprotein of the extracellular matrix that binds to membrane-spanning receptor proteins called integrins. In addition to integrins, fibronectin also binds extracellular matrix components such as collagen, fibrin and heparan sulfate proteoglycans...
and antithrombin
Antithrombin
Antithrombin is a small protein molecule that inactivates several enzymes of the coagulation system. Antithrombin is a glycoprotein produced by the liver and consists of 432 amino acids. It contains three disulfide bonds and a total of four possible glycosylation sites...
-1. Interactions between fibronectin and some syndecans can be modulated by the extracellular matrix
Extracellular matrix
In biology, the extracellular matrix is the extracellular part of animal tissue that usually provides structural support to the animal cells in addition to performing various other important functions. The extracellular matrix is the defining feature of connective tissue in animals.Extracellular...
protein tenascin
Tenascin
Tenascins are extracellular matrix glycoproteins. They are abundant in the extracellular matrix of developing vertebrate embryos and they reappear around healing wounds and in the stroma of some tumors.-Types:...
-C.
Family members and Structure
The syndecan protein family has four members. Syndecans 1 and 3 and syndecans 2 and 4, making up separate subfamilies, arose by geneGene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
duplication and divergent evolution from a single ancestral gene.
The syndecan numbers reflect the order in which the cDNAs for each family member were cloned. All syndecans have an N-terminal signal peptide
Signal peptide
A signal peptide is a short peptide chain that directs the transport of a protein.Signal peptides may also be called targeting signals, signal sequences, transit peptides, or localization signals....
, an ectodomain
Ectodomain
An ectodomain is the domain of a membrane protein that extends into the extracellular space . Ectodomains are usually the part of a protein that initiate contact with surface which leads to signal transduction. In SARS-CoV the ectodomain of the spike protein is responsible for attachment to and...
, a single hydrophobic transmembrane domain, and a short C-terminal cytoplasmic domain..All syndecans are anchored to plasma membrane via a 24-25 amino acid long hydrophobic transmembrane domain, in contrast to another type of cell surface proteoglycans that attaches to cell membrane using a glycosyl-phosphatidyl-inositol linkage .The most obvious differences between syndecans include
(together with differences in distribution) the subclassification
of the family depending on the existence of GAG binding
sites either at both ends of the ectodomain (syndecan-1 and -
3) or at the distal part only (syndecan-2 and -4) and a relatively
long Thr-Ser-Pro-rich area in the middle of syndecan-
3’s ectodomain .The ectodomains show the least amount of amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
sequence conservation
Conserved sequence
In biology, conserved sequences are similar or identical sequences that occur within nucleic acid sequences , protein sequences, protein structures or polymeric carbohydrates across species or within different molecules produced by the same organism...
, not more than 10–20%; in contrast, the transmembrane and cytoplasmic domains share approximately 60–70% amino acid sequence identity.
The transmembrane domains contain an unusual alanine/glycine sequence motif
Sequence motif
In genetics, a sequence motif is a nucleotide or amino-acid sequence pattern that is widespread and has, or is conjectured to have, a biological significance...
, while the cytoplasmic domain is essentially composed of two regions of conserved amino acid sequence
Conserved sequence
In biology, conserved sequences are similar or identical sequences that occur within nucleic acid sequences , protein sequences, protein structures or polymeric carbohydrates across species or within different molecules produced by the same organism...
(C1 and C2), separated by a central variable sequence of amino acids that is distinct for each family member (V).
In mammalian cells, syndecans are expressed by unique genes located on different chromosomes. This is general lack of evidence of alternate splicing in syndecan genes. All members of the syndecan family have 5 exons. The difference in size of the syndecans is credited to the variable length of exon 3, which encodes a spacer domain [1, 14]. In humans, the amino acid length of syndecan 1, 2, 3 and 4 is 310, 201, 346 and 198 respectively. Glycosaminoglycan chains, a member of the heparan sulfate group, are an important component of syndecan and are responsible for a diverse set of syndecan functions. The addition of glycosaminoglycans to syndecan is controlled by a series of post- translation events. The preferential site for the addition of glycosaminoglycans is on a serine residue followed by glycine residue, where the linker is attached for the elongation of the glycosaminoglycans by α-N-acetylglucosaminyltransferase I [1]. The linker is composed of four saccharides, first one being xylose, which is an unusual sugar in a unique place, attached to serine of the protein core and sequentially followed by two galactose and a β-D-glucuronic acid [1, 12].
Expression
Syndecans are expressed on the cell surface in a cell-specific manner. For example, in mouse cells and tissues, syndecan 1 is highly expressed in fibroblastic and epithelial cells. It is especially high in keratinocytes whereas low in endothelial and neural cells. These tissues include skin, liver, kidney and lungs. Syndecan 2 is highly expressed in endothelial, neural, and fibroblastic cells, whereas it has low expression levels in epithelial cells. It is specific to tissues such as the liver, endothelia and fibroblasts. Syndecan 3 is highly expressed in neural cells, but has low or undetectable amount in epithelial cells. In tissues, it is specific to the brain and expressed at low levels in liver, kidney, lung and small intestine. Syndecan 4 is highly expressed by epithelial and fibroblastic cells, but has low expression levels in neural and endothelial cells. In tissues, it is preferentially expressed in the liver and lungs [11].Functions
Functionality of syndecan is contributed by glycosaminoglycans which help in the interaction with different extracellular ligands. Depending upon the cellular localization of syndecan, glycosaminoglycans have different structures to accommodate the functional needs of the region.The syndecans are known to form homologous oligomers that may be important for their functions. Functions of syndecan can be categorized in four ways. First is growth-factor-receptor activation. Glycosaminoglycans attached to the syndecan help binding of the various growth factors for activation of important cellular signaling mechanisms. Growth factors such as bFGF, HGF, EGF, VEGF, neuregulins and others interact with syndecans [1, 2, 8]. For example, the ectodomain of syndecan 1 acts as an activator of FGF-2 for wound healing responses [13]. Second is matrix adhesion. Syndecans bind to structural extracellular matrix molecules such as collagens I, III, V, fibronectin, thrombospondin and tenascin to provide structural support for the adhesion [1, 2]. A third function is cell–cell adhesion. Evidence for syndecan’s role in cell–cell adhesion comes from the human myeloma cell line. These myeloma cells had a deficiency in the ability to adhere to one another in a rotation-mediated aggregation matrix. This deficiency is attributed to the lack of syndecan 1 expression. Syndecan 4 also interacts with integrinIntegrin
Integrins are receptors that mediate attachment between a cell and the tissues surrounding it, which may be other cells or the ECM. They also play a role in cell signaling and thereby regulate cellular shape, motility, and the cell cycle....
proteins for cell–cell adhesion [1, 2, 12]. A final role is in tumor suppression and progression. Syndecans act as tumor inhibitors by preventing cellular proliferation of tumor cell lines. For example, in the epithelial-derived tumor-cell line, S115, the syndecan 1 ectodomain suppresses the growth of S115 cells without affecting the growth of normal epithelial cells [7]. However, syndecan 1 expression also has a role in tumor progression in myeloma and other cancers [5, 6, 9, 15].
Osteoarthritis
Syndecan4 is upregulated in osteoarthritisOsteoarthritis
Osteoarthritis also known as degenerative arthritis or degenerative joint disease, is a group of mechanical abnormalities involving degradation of joints, including articular cartilage and subchondral bone. Symptoms may include joint pain, tenderness, stiffness, locking, and sometimes an effusion...
and inhibition of syndecan 4 reduces cartilage destruction in mouse models of OA.
Metabolic regulation and body composition
The Drosophila homologue dSdc and human SDC4 have been implicated in energy homeostasis.Multiple Myeloma
Syndecan1 is upregulated in Multiple MyelomaMultiple myeloma
Multiple myeloma , also known as plasma cell myeloma or Kahler's disease , is a cancer of plasma cells, a type of white blood cell normally responsible for the production of antibodies...
. High levels of shed syndecan1 in a patient's serum typically is correlated with poor prognosis.
Syndecan 1 is the most studied of all the syndecans in cancer research. Many studies have shown that syndecan 1 plays an important role in cancer progression, and also can be used as cancer biomarker. For example, syndecan 1 expression is higher in the bone marrow of the patients suffering from the multiple myeloma [9]. In one published study, the cells expressing the soluble syndecan 1 ectodomain promoted the growth and metastasis of B-lymphoid tumors more extensively than cells bearing surface syndecan 1 or lacking syndecan 1 expression [16]. Similarly, syndecan 1 expression has been linked with low differentiation in squamous cell carcinoma of the head and neck [15]. Syndecan 1 also has been linked with cancer progression by mediating the effects of growth factors in the cells. For example, syndecan 1 expression is increased in ductal breast carcinomas and is associated with factors of angiogenesis and lymphangiogenesis [5]. Studies from patients suffering from endometrial cancer have shown that these patients have increased syndecan 1 expression, and also that expression of this protein positively regulates the endometrial hyperplasia that can progress to endometrial cancer [6].