CD184 CXCR4 (chemokine [C-X-C motif] receptor 4) (* See available information under CD CKR), Fusin
Molecule TypeAntigen ExpressionMolecular Weight
Min / Max
Non-lineage Restricted Molecule
Type 3 glycoprotein, 7 span
Platelet
Chemokine Receptor
T Cell
B Cell
Monocyte
Dendritic Cell
Endothelial Cell
Thymus
Placenta
Brain
Spinal cord
Heart
Lung
Kidney
Pancreas
Leukocyte
Spleen
Liver
Skeletal muscle
Megakaryocyte
Macrophage
Granulocyte
Myeloid Cell
Hematopoietic Cell
Nonhematopoietic Cell
Neuron
Astrocyte
Spleen
Peripheral blood
Lymphoid Cell
Epithelial Cell
45 / 45

Expression
CD184 is widely expressed on blood and tissue cells, an unique feature of this chemokine receptor.  Hematopoietic lineage cells that are CD184+ includes B and T cells, monocytes/macrophages, dendritic cells, granulocytes, megakaryocytes/platelets, lymphoid and myeloid precursor cells, non-hematopoietic cells such as endothelial and epithelial cells, and astrocytes and neurons among other tissue cells.  Stimulation of T cells with PHA, IL-2, or with a combination of anti-CD3 and anti-CD28 antibodies results in transient upregulation of CD184 mRMA, which is reversed to base-levels upon prolonged in greater than 3 days cell culture.  IL-4, TGFb and FGF stimulate expression of CD184.  IFN╬│ and TNFa inhibit their stimulatory activity on T cells, monocytes/macrophages, dendritic cells and endothelial cells.  These stimulatory and inhibitory effects on CD184 gene transcription and/or CD184 mRNA stability clearly differ from the rapid downmodulation of the cell surface CD184 by SDF-1 and T cell stimuli.  CD184 is expressed in numerous tissues, such as perpherial blood leukocytes, spleen, thymus, spinal cord, heart, placenta, lung, liver, skeletal muscle, kidney, pancreas, cerebullum, cerebral cortex and medulla.  Expression is also in the brain microvascular, coronary artery and umbilical cord endothelial cells.

Structure
MOLECULAR FAMILY NAME: Belongs to the chemokine receptor family.

CD184 is a multi-pass type-3, 7 span 352 aa glycoprotein.  It contains an extracellular domain which contains 2 potential N-glycosylation sites, 7 transmembrane-spanning domains and a cytoplasmic carboxyl terminal domain.  CD184 is a chemokine receptor which are G-protein coupled receptors and form a division of the leukocyte chemoattractant subfamily which is part of the rhodopsin family of GPCRs.  CD184 has a specificity for 1 CXC-motif chemokine, called stromal cell-derived factor 1 (SDF-1).  SDF-1 exists in 2 structural variant forms, SDF-1a and SDF-1b that differ by 4 aa in the carboxyl-terminus of the b-form but show an identical receptor binding and activity profiles.  Orthologue CD184 cDNAs are described in numerous species, including monkeys, rats, mice, cats, cattle and fish.  The 352 aa CD184 has 5 aa are on exon 1 and the residual 347 aa are on exon 2.  The CD184 promoter contains 1 TATA box, 2 GC boxes and 1 potential nuclear respiratory factor (NRF)-1 binding site.  Gene expression is enhanced by T cell activation with antibodies to CD3 and CD28, phytohemagglutinin (PHA), phorbolesters (PMA)/ionomycin and proliferation of IL-2 factors.  The major transcript in human and mouse is 1.7 kb-1.9 kb but the splice variants encoding CD184 polypeptides with alternative amino-terminal regions are also known.

MOLECULAR MASS

Cell Type Unreduced Reduced
45 kDa

The CD184 polypeptide has a of Mr 39'745 aa backbone.

POST-TRANSCRIPTIONAL MODIFICATION

Alternative splicing yields 2 different isoforms.  CD184 variant proteins are encoded by an alternatively spliced mRNA.  In the human CXCR4-low the amino-terminal Met-Glu-Gly-Ile-Ser sequence of CD184 is replaced by Met-Ser-Ile-Pro-Leu-Pro-Leu-Leu-Gln and murine CXCR-4B differs from murine CD184 by the deletion of Val6-Ser7.

POST-TRANSLATIONAL MODIFICATION OF CD184

The human CD184 has 2 potential N-linked glycosylation sites.  The 1st 1 is in the amino-terminal region Asn11-Tyr-THr and the 2nd is in the extracellular loop Asn177-Val-Ser.  Human CD184 has numerous Ser/Thr phosphorylation sites in the intracellular regions.


Ligands
LIGANDS AND MOLECULES ASSOCIATED WITH CD184

CD184 associates with SDF-1 (CXCL12) and is a coreceptor for HIV.

LIGANDS AND MOLECULES ASSOCIATED WITH CD184
Molecule Comment
X4 HIV envelope glycoprotein gp120 Binds to CD184 and induces signaling
Heterotrimeric G proteins First group of elements that becomes activated during CD184-mediated signal transduction


Function
CD184 is the receptor for the CXC chemokine SDF-1. CD184 transduces a signal by increasing the intracellular calcium ion level.  It mediates blood cell migration in response to SDF-1 and is involved in B lympho- and myelopoiesis, cardiogenesis, blood vessel formation and cerebellar development.  Although ubiquitously expressed in blood and tissue cells, its role in blood and tissue homeostatis is not understood.  As a member of the family of chemokine receptors, CD184 mediates blood cell migration in response to SDF-1.  CD184 functions include co-stimulation in pre-B cell proliferation, induction of apoptosis and HIV entry.  The unusual wide range of transcript expression is a hallmark of CD184 and includes blood progenitor cells as well as mature blood and tissue cells.  In leukocytes, immediate responses to CD184 activation include chemotactic migration that depends on cytoskeletal rearrangement and integrin-mediated adhesion.  Signal transduction elements include focal adhesion components and diverse kinases such as RAFTK/Pyk2, paxillin, Crk, and PI-3 kinases that are critical for CD184 internalization and cell migration as well as further downstream elements, such as mitogen-activated protein kinases ERK1/2.  CD184 mediates chemotaxis in mature and progenitor blood cells and, together with its ligand SDF-1, is essential for B lympho- and myelopoiesis.  In addition to hematopoiesis, CD184 is responsible for cardiac ventricular septum formation and vascularization of the gastrointestinal tract probably by regulating vascular branching and/or remodeling processes in endothelial cells.  It is also responsible for the development of cerebellar granule cells.  The function of CD184 and SDF-1 in mature blood and tissue cells is not fully understood but is most likely unrelated to inflammation.  CD184 is 1 of the 2 major HIV/SIV co-receptors.

BIOCHEMICAL ACTIVITY

CD184 induces cellular responses through coupling to Bordetella  pertussis toxin-sensitive heterotrimeric G proteins.

DISEASE RELEVANCE AND FUNCTION OF CD184 IN INTACT ANIMAL

Homozygous CD184 knockout mice die prenatally, E15-E18, or within hours after birth.  Phenotypic aberrations in homozygous CD184 knockout mice include defects in B lympho- and myelopoiesis, heart and cerebellar development, and vascularization of the gastrointestinal tract.  This phenotype fully matches the one seen in mice lacking SDF-1, demonstrating the monogamous relationship between CD184 and SDF-1.  In the human, CD184 may also be critically involved in hematopoiesis and in cardiac ventricular septum formation, as suggested by numerous in vitro studies and the unusual high degree of sequence conservation between mouse and human CD184 and SDF-1.  Stromal cell-derived SDF-1 may support hematopoiesis by attraction and proper localization of early blood progenitor cells that require stromal cell contact for development.  SDF-1 may enhance the IL-7 effect on CD184-positive B cell precursors.  SDF-1 may also direct platelet generation during transendothelial migration of megakaryocytes.  All types of mature blood cells, including monocytes, granulocytes, T and B lymphocytes, express CD184 and respond to SDF-1, suggesting that the CD184/SDF-1 system may control blood cell homeostasis.  There is no evidence for the CD184/SDF-1 system involvement in inflammatory processes.  A chemokine-unrelated function is the co-receptor function of CD184 for certain X4-tropic HIV variants that are preferentially found in infected individuals with AIDS.  HIV variants that are efficiently transmitted and predominate during the asymptomatic stages require the chemokine receptor CCR5 and are called R5-tropic.  The prevalent intracellular localization of CD184 in HIV targets cells, possibly caused by locally produced SDF-1, may contribute to the efficiency in transmission and propagation of X4-tropic viruses.  CD184 could be involved in cerebellar development and in CNS, could mediate hippocampal-neuron survival.  CD184 acts with the CD4 protein to support HIV entry into cells and is also highly expressed in breast cancer cells.  Mutations in this gene have been associated with WHIM (warts, hypogammaglobulinemia, infections and myelokathexis) syndrome.

Comments
MOLECULAR INTERACTIONS -
PROTEINS AND DNA ELEMENTS WHICH REGULATE TRANSCRIPTION OF CD184: No information.

SUBSTRATES: No information.

ENZYMES WHICH MODIFY CD184: No information.

ADDITIONAL INSIGHTS

In blood and tissue leukocytes, CD184 is predominantly stored in intracellular compartments.  A high-level cell surface expression is rapidly achieved during cell culture.  Preferential intracellular accumulation of CD184 in blood and tissue cells suggest that the cell surface CD184 is downmodulated by locally produced SDF-1 or other agents.  SDF-1 binding induces CD184 phosphorylation by Ser/Thr kinases which leads to CD184 internalization via clathrin-coated pits.  The internalization is reversed within 30-60 minutes after the removal of SDF-1 from the culture medium.  Down modulation of CD184 on lymphocytes is also achieved through CD184-unrelated stimuli, including PMA, PHA and antibodies to T cell receptor or co-stimulatory molecules.

  

Database accession numbers
AnimalPIRSWISSPROTEMGBL/GENBANK
 
HumanEntrezgene 7852P61073
Antibodies
12G5   View Reactivity

Revised June 25, 2008


Contact us: Webmaster |  509-335-9515 | Accessibility | Copyright | Policies
College of Veterinary Medicine Washington State University, Pullman, WA, 99164-7010 USA
Copyright 1995-2003 Washington State University