CD126 IL-6R (α chain), IL-6Rα
Molecule TypeAntigen ExpressionMolecular Weight
Min / Max
Non-lineage Restricted Molecule
Type 1 glycoprotein
Plasma Cell
B Cell
Myeloma
Fibroblast
Epithelial Cell
Hepatocyte
Neural Cell
Nonhematopoietic Cell
T Cell
Monocyte
80 / 80

Expression
CD126 is expressed on T cells, monocytes, activated B cells and myelomas.  Expression is found on neoplastic plasma cells and not on normal plasma cells which express CD126. It is also present at lower levels on epithelial cells, fibroblasts, hepatocytes and neural cells, and on some other non-hematopoietic cells.



Structure
MOLECULAR FAMILY NAME: Belongs to the hematopoietin superfamily.

CD126 is a single-pass type-1 a chain 468 aa glycopeptide.  It contains a 19 aa signal peptide, a 339 aa extracellular region which contains a N-terminal Ig-like C2-type domain followed by 2 fibronectin type-3 modules which forms a cytokine receptor family domain which has conserved cysteines in the N-terminal and a WSXWS motif and 4 potential N-linked glycosylation sites, a 28 aa transmembrane region and an 82 aa intracellular cytoplasmic domain which is nonessential for receptor complex formation and signal transduction but does contain a tyrosine-based and dileucine-type motif required for direct sorting of CD126 to the basolateral membrane of polarized cells.  The functional high affinity receptor for human IL-6 is formed by the non-covalent association of 2 subunits, CD126 and CD130.  CD126 is a cytokine receptor belonging to the hematopoietin receptor superfamily and the Ig gene syperfamily.

MOLECULAR MASS
Cell Type Unreduced Reduced
T cell, monocytes, hepatocytes, etc. 80 kDa 80 kDa

POST-TRANSCRIPTIONAL MODIFICATION

Alternative splicing yields 2 different isoforms.  A splicing variant having no transmembrane domain is present and generates a soluble form of the receptor able to bind with IL-6 and mediate its activity by associating with CD130.

POST-TRANSLATIONAL MODIFICATION

CD126 is modified by glycosylation of ~30 kDa.  A certain proportion of the mature protein undergoes proteolytic cleavage to form the soluble receptor able to bind with IL-6R and mediate its activity by associating with CD130.

Ligands
LIGANDS AND MOLECULES ASSOCIATED WITH CD126

CD126 binds IL-6R with a low affinity of kDa = 1 nM.  CD130 binding stabilizes the CD126/IL-6R complex resulting in the formation of a high-affinity receptor of kDa = 10 pM.
 
Molecule Comment
IL-6R The only known ligand for CD126
CD130 (gp130) CD126 associates with gp130 (CD130) after binding to IL-6R



Function
CD126 is a potent pleiotropic cytokine that regulates cell growth and differentiation and plays a role in immune response.  The growth factor appears on myelomas, B cell hybridomas, activated and EBV-transformed B cells and T cell lines.  CD126 also induces proliferation of hematopoietic precursors, mediates the acute phase response in the liver and of hepatocytes and affects differentiation of neural cell lines.  CD126 binds the cytokine IL-6 and then associates with CD130 homodimers to form the functional Il-6R which mediates the biological activities of IL-6.  The ability of soluble CD126 to bind IL-6 and associates with membrane bound CD130 to form a functional receptor is a rare example of a soluble receptor-cytokine complex capable of acting as an agonist rather than antagonistically.  However, this complex can act antagonistically when it binds soluble CD130.  IL-6 is essential for differentiation of normal B cells into plasma cells and is an essential survival factor for circulating plasma cell precursors.

CD126 is an endothelial marker used to separate circulating endothelial cells from blood, a subset of which are endothelial progenitors that are involved in angiogenesis and a promsing tool in the diagnosis, prognosis and therapy of vascular disorders.

BIOCHEMICAL ACTIVITY

No biochemical activity is shown.

DISEASE RELEVANCE AND FUNCTION OF CD126 IN INTACT ANIMAL

CD126 is an endothelial marker used to separate circulating endothelial cells from blood, a subset of which are endothelial progenitors that are involved in angiogenesis and a promising tool in the diagnosis, prognosis and therapy of vascular disorders.  CD126 (anti-IL-6R) is a therapeutic agent for chronic inflammatory conditions, including Crohn's disease, rheumatoid arthritis, Castleman's disease and juvenile idiopathoc arthritis.  Dysregulated production of IL-6 and CD126 are also implicated in the pathogenesis of multiple myeloma, autoimmune diseases,  prostate cancer.  The function of dysregulated autocrine or paracrine stimulation has been suggested for the generation of myeloma and plasmacytomas.  Ectopic and/or continuous expression of the ligand for CD126 causes hypergamma globulinemia, glomerular proliferative nephritis and lymphoid infiltration in some organs.  Shedding of IL-6R (gp80) determines the ability of IL-6R to induce CD130 phosphorylation in human osteoblasts.  Continuous stimulation of CD130 by IL-6 and soluble CD126 leads to massive extramedullary hematopoiesis.  IL-6 is a growth factor for myelomasw, including hybridomas and a stimulus for the acute phase response in the liver.

Comments
MOLECULAR INTERACTIONS -
PROTEINS AND DNA ELEMENTS WHICH REGULATE TRANSCRIPTION OF CD126: No information.

SUBSTRATES

CD126 is not an enzyme.

ENZYMES WHICH MODIFY CD126
Molecule Comment
Unknown metalloprotease Attacks CD126 and produces a biologically active extracellular soluble form

ADDITIONAL INSIGHTS

A soluble form of CD126 in the complex with IL-6R stimulates cells that express only gp130. Such cells in the absence of soluble CD126 would not be responsive to IL-6R. This mechanism is called trans-signaling.

Database accession numbers
AnimalPIRSWISSPROTEMGBL/GENBANK
 
HumanEntrezgene 3570P08887
MouseJL0145P22272X51975
RatA37986P22273J05668
Antibodies

Revised June 25, 2008


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