Syndecans are single
transmembrane
A transmembrane protein (TP) is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequentl ...
domain
Domain may refer to:
Mathematics
*Domain of a function, the set of input values for which the (total) function is defined
**Domain of definition of a partial function
**Natural domain of a partial function
**Domain of holomorphy of a function
* Do ...
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
s that are thought to act as coreceptors, especially for
G protein-coupled receptor
G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...
s. More specifically, these core proteins carry three to five
heparan sulfate
Heparan sulfate (HS) is a linear polysaccharide found in all animal tissues. It occurs as a proteoglycan (HSPG, i.e. Heparan Sulfate ProteoGlycan) in which two or three HS chains are attached in close proximity to cell surface or extracellular ma ...
and
chondroitin sulfate
Chondroitin sulfate is a sulfated glycosaminoglycan (GAG) composed of a chain of alternating sugars ( N-acetylgalactosamine and glucuronic acid). It is usually found attached to proteins as part of a proteoglycan. A chondroitin chain can have ove ...
chains, i.e. they are
proteoglycans
Proteoglycans are proteins that are heavily glycosylated. The basic proteoglycan unit consists of a "core protein" with one or more covalently attached glycosaminoglycan (GAG) chain(s). The point of attachment is a serine (Ser) residue to whic ...
, which allow for interaction with a large variety of ligands including
fibroblast growth factor
Fibroblast growth factors (FGF) are a family of cell signalling proteins produced by macrophages; they are involved in a wide variety of processes, most notably as crucial elements for normal development in animal cells. Any irregularities in the ...
s,
vascular endothelial growth factor
Vascular endothelial growth factor (VEGF, ), originally known as vascular permeability factor (VPF), is a signal protein produced by many cells that stimulates the formation of blood vessels. To be specific, VEGF is a sub-family of growth factors, ...
,
transforming growth factor Transforming growth factor (, or TGF) is used to describe two classes of polypeptide growth factors, TGFα and TGFβ.
The name "Transforming Growth Factor" is somewhat arbitrary, since the two classes of TGFs are not structurally or genetically rel ...
-beta,
fibronectin
Fibronectin is a high- molecular weight (~500-~600 kDa) glycoprotein of the extracellular matrix that binds to membrane-spanning receptor proteins called integrins. Fibronectin also binds to other extracellular matrix proteins such as collage ...
and
antithrombin
Antithrombin (AT) is a small glycoprotein that inactivates several enzymes of the coagulation system. It is a 432-amino-acid protein produced by the liver. It contains three disulfide bonds and a total of four possible glycosylation sites. α-An ...
-1. Interactions between fibronectin and some syndecans can be modulated by the
extracellular matrix
In biology, the extracellular matrix (ECM), also called intercellular matrix, is a three-dimensional network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide stru ...
protein
tenascin C
Tenascin C (TN-C) is a glycoprotein that in humans is encoded by the ''TNC'' gene. It is expressed in the extracellular matrix of various tissues during development, disease or injury, and in restricted neurogenic areas of the central nervous sys ...
.
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
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
duplication and divergent evolution from a single ancestral gene.
The syndecan numbers reflect the order in which the
cDNA
In genetics, complementary DNA (cDNA) is DNA synthesized from a single-stranded RNA (e.g., messenger RNA (mRNA) or microRNA (miRNA)) template in a reaction catalyzed by the enzyme reverse transcriptase. cDNA is often used to express a speci ...
s for each family member were
cloned
Cloning is the process of producing individual organisms with identical or virtually identical DNA, either by natural or artificial means. In nature, some organisms produce clones through asexual reproduction. In the field of biotechnology, c ...
. All syndecans have an N-terminal
signal peptide
A signal peptide (sometimes referred to as signal sequence, targeting signal, localization signal, localization sequence, transit peptide, leader sequence or leader peptide) is a short peptide (usually 16-30 amino acids long) present at the N-ter ...
, an
ectodomain
An ectodomain is the domain of a membrane protein that extends into the extracellular space (the space outside a cell). Ectodomains are usually the parts of proteins that initiate contact with surfaces, which leads to signal transduction.A notable ...
, a single
hydrophobic
In chemistry, hydrophobicity is the physical property of a molecule that is seemingly repelled from a mass of water (known as a hydrophobe). In contrast, hydrophiles are attracted to water.
Hydrophobic molecules tend to be nonpolar and, th ...
transmembrane domain
A transmembrane domain (TMD) is a membrane-spanning protein domain. TMDs generally adopt an alpha helix topological conformation, although some TMDs such as those in porins can adopt a different conformation. Because the interior of the lipid bil ...
, and a short C-terminal
cytoplasmic
In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. Th ...
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
proteoglycan
Proteoglycans are proteins that are heavily glycosylated. The basic proteoglycan unit consists of a "core protein" with one or more covalently attached glycosaminoglycan (GAG) chain(s). The point of attachment is a serine (Ser) residue to whic ...
s 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
Syndecan 1 is a protein which in humans is encoded by the ''SDC1'' gene. The protein is a transmembrane (type I) heparan sulfate proteoglycan and is a member of the syndecan proteoglycan family. The syndecan-1 protein functions as an integral m ...
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 acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...
sequence
conservation
Conservation is the preservation or efficient use of resources, or the conservation of various quantities under physical laws.
Conservation may also refer to:
Environment and natural resources
* Nature conservation, the protection and managem ...
, 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
In biology, a sequence motif is a nucleotide or amino-acid sequence pattern that is widespread and usually assumed to be related to biological function of the macromolecule. For example, an ''N''-glycosylation site motif can be defined as ''As ...
, 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
, 14
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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
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
, 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
1
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
FGF2
Fibroblast growth factor 2, also known as basic fibroblast growth factor (bFGF) and FGF-β, is a growth factor and signaling protein encoded by the ''FGF2'' gene. It binds to and exerts effects via specific fibroblast growth factor receptor ''(FG ...
,
HGF, EGF, VEGF, neuregulins and others interact with syndecans
, 2, 8
The comma is a punctuation mark that appears in several variants in different languages. It has the same shape as an apostrophe or single closing quotation mark () in many typefaces, but it differs from them in being placed on the baseline ...
For example, at the site of tissue injury, the soluble syndecan-1 ectodomains are cleaved by heparanases, producing heparin-like fragments that activate bFGF
3 Whereas most growth factors interact with syndecans via heparan sulfate chains, the prosecretory mitogen
lacritin
Lacritin is a 12.3 kDa glycoprotein encoded in humans by the ''LACRT'' gene. Lacritin's discovery emerged from a screen for factors that stimulate tear protein secretion. Lacritin is a secreted protein found in tears and saliva. Lacritin also pro ...
requires
heparanase
Heparanase, also known as HPSE, is an enzyme that acts both at the cell-surface and within the extracellular matrix to degrade polymeric heparan sulfate molecules into shorter chain length oligosaccharides.
Synthesis and structure
The protein ...
to both expose and create a binding site in the N-terminus of syndecan 1.
[ubMed - indexed for MEDLINE>]
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
, 2
The comma is a punctuation mark that appears in several variants in different languages. It has the same shape as an apostrophe or single closing quotation mark () in many typefaces, but it differs from them in being placed on the baseline ...
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
integrin
Integrins are transmembrane receptors that facilitate cell-cell and cell-extracellular matrix (ECM) adhesion. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular signals such as regulation of the cell cycle, ...
proteins for cell–cell adhesion
, 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
However, syndecan 1 expression also has a role in tumor progression in myeloma and other cancers
, 6, 9, 15
It associates with intracellular actin cytoskeleton and helps maintain normal epithelium sheet morphology
Protein Domains
The syndecan proteins can contain the following protein domains,
*A signal sequence;
*An extracellular domain (ectodomain) of variable length whose sequence is not evolutionarily conserved in the various forms of syndecans. The ectodomain contains the sites of attachment of the heparan sulphate glycosaminoglycan side chains;
*A transmembrane region;
*A highly conserved cytoplasmic domain of about 30 to 35 residues, which could interact with cytoskeletal proteins.
Clinical significance
Endometriosis
Syndecan-4 is upregulated in
endometriosis
Endometriosis is a disease of the female reproductive system in which cells similar to those in the endometrium, the layer of tissue that normally covers the inside of the uterus, grow outside the uterus. Most often this is on the ovaries, f ...
and inhibition of syndecan-4 in human endometriotic cells results in a reduction of invasive growth
in vitro
''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in biology an ...
and changes in
matrix metalloproteinase
Matrix metalloproteinases (MMPs), also known as matrix metallopeptidases or matrixins, are metalloproteinases that are calcium-dependent zinc-containing endopeptidases; other family members are adamalysins, serralysins, and astacins. The MMPs b ...
expression.
Osteoarthritis
Syndecan-4 is upregulated in
osteoarthritis
Osteoarthritis (OA) is a type of degenerative joint disease that results from breakdown of joint cartilage and underlying bone which affects 1 in 7 adults in the United States. It is believed to be the fourth leading cause of disability in the w ...
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 myeloma
Multiple myeloma (MM), also known as plasma cell myeloma and simply myeloma, is a cancer of plasma cells, a type of white blood cell that normally produces antibodies. Often, no symptoms are noticed initially. As it progresses, bone pain, an ...
. 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
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
6 Similarly, syndecan 1 expression has been linked with low differentiation in squamous cell carcinoma of the head and neck
5
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
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
References
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* {{cite journal , year = 2002 , title = Soluble syndecan-1 promotes growth of myeloma tumors in vivo , journal = Blood , volume = 100 , issue = 2, pages = 610–617 , doi = 10.1182/blood.V100.2.610 , pmid = 12091355 , last1 = Yang , first1 = Y , last2 = Yaccoby , first2 = S , last3 = Liu , first3 = W , last4 = Langford , first4 = JK , last5 = Pumphrey , first5 = CY , last6 = Theus , first6 = A , last7 = Epstein , first7 = J , last8 = Sanderson , first8 = RD , doi-access = free
External links
MBInfo: Syndecans
Proteoglycans
Single-pass transmembrane proteins