|Molecule Type||Antigen Expression||Molecular Weight|
Min / Max
|Non-lineage Restricted Molecule|
Type 1 glycoprotein
|140 / 140|
|CD124 (IL-4R) is expressed on mature B and T cells, hematopoietic precursors, fibroblasts, epithelial and endothelial cells. The expression on B cells is upregulated by LPS, anti-IgM or IL-4R and on resting T cells it is increased by stimulation with ConA or IL-4R. CD124 is expressed on hemopoietic and non-hemopoietic cells expressing IL-4R at relatively low numbers of 100-10,000 molecules of IL-4R per cell. CD124 is expressed at low levels in humans but is upregulated in activated T and B lumphocytes.|
|MOLECULAR FAMILY NAME: Belongs to the hemopoietin family.|
CD124 is a single-chain type-1 a chain 825 aa glycopeptide. It contains a 25 aa signal sequence, a 207 aa extracellular domain which contains a cytokine receptor domain, 4 conserved cysteines and a Tyr-Ser-X-Trp-Ser WSXWS motif containing a fibronectin type-3 domain and has 6 potential N-glycosylation sites, a 24 aa transmembrane region and a 569 aa intracellular cytoplasmic domain which is rich in serines and has a proline-rich box region required for association of Janus tyrosine kinases that recruit downstream signaling molecules and 5 conserved tyrosines. CD124 associates with CD132 to form a heterodimeric receptor complex at the cell surface. In addition a 2nd type of IL-4R is formed through the association of CD124 and the IL-13Ra chain. A soluble form of the mouse IL-4R is produced by alternative splicing of CD124. The IL-13Ra chain shows structural homology to CD125 IL-5R a chain with a 51% aa sequence similarity and a 27% identity. Similar to CD125, the extracellular region of the IL-13Ra chain consists of a N-terminal region of about 100 aa with a sequence similarity to the equivalent portion of CD123, the IL-3Ra chain, and CD116, the GM-CSFR a chain, followed by a cytokine receptor domain and a fibronectin type 3 domain that includes the WSXWS motif. CD124 is a cytokine receptor belonging to the hemopoietic receptor superfamily and the Ig gene superfamily.
Alternative splicing yields 2 different isoforms, a membrane-bound and a soluble form. The soluble IL-4R is produced in the mouse system by splicing or by proteolysis of the membrane-bound protein and this soluble form can inhibit IL-4-mediated cell proliferation and CD125 (IL-5) upregulation by T-cells.
CD124 contains a signal sequence of 25 aa in the N terminal domain and 6 potential sites for N-linked glycosylation in the extracellular domain.
|LIGANDS AND MOLECULES ASSOCIATED WITH CD124|
CD124 binds IL-4Rs with a high affinity of kDa = 50-100 pM and may be composed of CD124/CD132 or CD124/IL-13R a chain. IL-4 induced signal transduction involves IL-4R binding and activation of 2 Janus family Tyr kinases, Jak1 and Jak3. These Tyr kinases activate signal transducers and activator of transcription Stat proteins denoted as IL-4R Stat(s) in the case of IL-4R. IL-4R induces association of PI-3 kinase with the mouse IL-4R.
CD213a1 and CD213a2 binds the human IL-13R a chain expressed in COS-7 cells and binds human IL-13R with a high affinity of kDa = 220-280 pM, whereas COS-7 cells transfected with the mouse IL-13R a chain, cDNA bind mouse IL-13R with a low affinity of kDa = 2-10 nM. In both species, the IL-13R a chain also associates with CD124 to form a receptor capable of binding both IL-13R and IL-4R with a high affinity and with mediating signal transduction events. This interaction may explain the apparent discrepancy in the ability of human, but not the mouse, for the IL-13R a chain to bind IL-13R with a high affinity. Since untransfected COS-7 cells express low levels of CD124 which might associate with transfected human, but not mouse, the IL-13R a chain forms a functional high affinity binding site for IL-13R. Crosslinking experiments have identified an IL-13R binding protein of approximately 60 kDa-70 kDa, which probably corresponds to the IL-13R a chain.
|CD124 associates with CD132 (the common γ chain) to form the type IL-4 receptor. The association of CD124 and CD213 (IL-13Rα1) forms the type-2 IL-4 receptor and the functional IL-13 receptor. Although CD124 is part of the CD213 receptor, CD213 binds IL-13Ra1 and not CD124. IL-4 and IL-13 signaling is mediated via CD124 results in the activation of JAK/STST and insulin receptor substrate 1 and 2 pathways. IL-4 and IL-13 have similar effects on B cells including proliferation, IgE and IgG4 class switching, in combination with CD40/CD40 ligand costimulation and induce expression of surface antigens, including CD23 (low affinity IgE receptor) and MHC class II. CD124 is important in inducing Th2 cells and contributes to allergic bronchial inflammation and CD213 promotes inflammation in allergic disorders. CD124 is a cytokine produced by T cells that regulates proliferation and differentiation of a variety of cells and modulates the activity of these cells following binding to cell surface receptors. It is a growth factor for pre-activated B and T cells and enhances IgG1 and IgE production, differentiation of TH2-type CD4+ T cells and the expression of MHC class II molecules on B cells and macrophages. CD124 also induces macrophage activation and synergizes with colony-stimulating factors in promoting the growth of hematopoietic cells. In monocytes and macrophages, IL-13 enhances the expression of MHC class II, CD23 and integrins involved in adhesion including CD11b, CD11c, CD18 and CD29. IL-13 inhibits the production of several pro-inflammatory mediators, including prostaglandins, reactive oxygen, nitrogen intermediates, IL-1, -6, -8, -12 and TNF-α by monocytes and macrophages. IL-13 is potent inducer of VCAM-1, expression of endothelial cells, induces proliferation and cholinergic contraction of smooth muscle cells in vitro, and promotes type-1 collagen synthesis in human dermal fibroblasts. IL-4R and IL-13R induce Tyr phosphorylation of CD124.|
BIOCHEMICAL ACTIVITY: No information.
DISEASE RELVELANCE AND FUNCTION OF CD124 IN INTACT ANIMAL
CD124 is a therapeutic target in the treatment of bronchial asthma and malignancies. Apart from its role in asthma, IL-13 contributes to the control of helminth infections and suppresses inflammation associated with bacterial and viral diseases. Variations of CD124 have been associated with atopy, a condition that can manifest itself as allergic rhinitis, sinusitus, asthma or eczema. IL-13 mediated stimulation of respiratory epithelial cells results in chemokine expression, altered mucociliary differentiation, decreased ciliary beat frequency of ciliated epithelium, and gobley cell metaplasia, demonstrating IL-13 to be an important effector molecule in asthma and obstructive pulmonary diseases. The CD124 gene targeting mice showed autoimmune disease. IL-4R, the ligand of CD124, plays an important role in the induction of Th2 T cells and IgE class switch. Internalization of the IL-4R a increases cytotoxic effect of IL-4R targeted cytotoxin in cancer cells.
|The soluble form of mouse IL-4R binds IL-4 with a high affinity, inhibits the biological activity of IL-4R and prevents the degradation of the cytokine. A recombinant extracellular domain of the human IL-4R is a powerful antagonist of its specific ligand. The human and mouse IL-13Ra chain sequences share the same overall topology, but they show only a limited aa sequence identity. It remains to be determined whether additional IL-13R subunits exist and whether, in fact, these molecules are true species orthologues. |
MOLECULAR INTERACTIONS -
PROTEINS AND DNA ELEMENTS WHICH REGULATE TRANSCRIPTION OF CD124: No information.
SUBSTRATES: No information.
ENZYMES WHICH MODIFY CD124: No information.
Database accession numbers
Revised June 25, 2008