C-X-C chemokine receptor type 4 (CXCR-4) also known as fusin or CD184 (cluster of differentiation 184) is a protein that in humans is encoded by the CXCR4 gene.

The protein is a CXC chemokine receptor.

Gene location Chromosome 2 

CXCR4 is a protein that belongs to the chemokine receptor family.

It is encoded by the CXCR4 gene and is primarily found on the surface of immune cells, such as T cells and monocytes.

CXCR4 plays a crucial role in cell migration and is involved in various physiological processes, including immune response, hematopoiesis, and development of the central nervous system.

It is also known to be a co-receptor for the human immunodeficiency virus (HIV) entry into target cells.

CXCR-4 is an alpha-chemokine receptor specific for stromal-derived-factor-1 (SDF-1 also called CXCL12), a molecule endowed with potent chemotactic activity for lymphocytes. 

CXCR4 is one of several chemokine co-receptors that HIV can use to infect CD4+ T cells. 

HIV isolates that use CXCR4 are traditionally known as T-cell tropic isolates. 

Typically, these viruses are found late in infection. 

CXCR4 is upregulated during the implantation window in natural and hormone replacement therapy cycles in the endometrium, producing, in presence of a human blastocyst, a surface polarization of the CXCR4 receptors suggesting that this receptor is implicated in the adhesion phase of human implantation.

CXCR4’s ligand SDF-1 is known to be important in hematopoietic stem cell homing to the bone marrow.

CXCR4 signalling regulates the expression of CD20 on B cells. 

SDF-1 and CXCR4 are  relatively a ligand-receptor pair, and recent evidence demonstrates ubiquitin is also a natural ligand of CXCR4.

Ubiquitin is a small (76-amino acid) protein highly conserved among eukaryotic cells. 

It is best known for its intracellular role in targeting ubiquitylated proteins for degradation via the ubiquitin proteasome system. 

Evidence suggests ubiquitin is anti-inflammatory immune modulator and endogenous opponent of proinflammatory damage associated molecular pattern molecules.

CXCR4 is present in newly generated neurons during embryogenesis and adult life where it plays a role in neuronal guidance. 

The levels of the receptor decrease as neurons mature. 

CXCR4 dimerization is dynamic and increases with concentration.

Drugs that block the CXCR4 receptor appear to be capable of mobilizing hematopoietic stem cells into the bloodstream as peripheral blood stem cells. 

Peripheral blood stem cell mobilization is very important in hematopoietic stem cell transplantation and is currently performed using drugs such as G-CSF. 

G-CSF is a growth factor for neutrophils, and may act by increasing the activity of neutrophil-derived proteases such as neutrophil elastase in the bone marrow leading to proteolytic degradation of SDF-1. 

Plerixafor is a drug that directly blocks the CXCR4 receptor. 

Plerixafor is a very efficient inducer of hematopoietic stem cell mobilization.

It has been associated with WHIM syndrome.

WHIM like mutations in CXCR4 were recently identified in patients with Waldenström’s macroglobulinemia, a B-cell malignancy.

The presence of CXCR4 WHIM mutations has been associated with clinical resistance to ibrutinib in patients with Waldenström’s macroglobulinemia.

CXCR4’s expression is low or absent in many healthy tissues.

It is expressed in over 23 types of cancer, including breast cancer, ovarian cancer, melanoma, and prostate cancer. 

The expression of this receptor in cancer cells has been linked to metastasis to tissues containing a high concentration of CXCL12, such as lungs, liver and bone marrow.

However, in breast cancer where SDF1/CXCL12 is also expressed by the cancer cells themselves along with CXCR4, CXCL12 expression is positively correlated with disease free survival. 

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