Family

CXC chemokine receptor 4 (IPR001277)

Short name: Chemokine_CXCR4

Family relationships

Description

Chemokines (chemotactic cytokines) are a family of chemoattractant molecules. They attract leukocytes to areas of inflammation and lesions, and play a key role in leukocyte activation. Originally defined as host defense proteins, chemokines are now known to play a much broader biological role [PMID: 11544102]. They have a wide range of effects in many different cell types beyond the immune system, including, for example, various cells of the central nervous system [PMID: 9689100], and endothelial cells, where they may act as either angiogenic or angiostatic factors [PMID: 7592998].

The chemokine family is divided into four classes based on the number and spacing of their conserved cysteines: 2 Cys residues may be adjacent (the CC family); separated by an intervening residue (the CXC family); have only one of the first two Cys residues (C chemokines); or contain both cysteines, separated by three intervening residues (CX3C chemokines).

Chemokines exert their effects by binding to rhodopsin-like G protein-coupled receptors on the surface of cells. Following interaction with their specific chemokine ligands, chemokine receptors trigger a flux in intracellular calcium ions, which cause a cellular response, including the onset of chemotaxis. There are over fifty distinct chemokines and least 18 human chemokine receptors [PMID: 10714678]. Although the receptors bind only a single class of chemokines, they often bind several members of the same class with high affinity. Chemokine receptors are preferentially expressed on important functional subsets of dendritic cells, monocytes and lymphocytes, including Langerhans cells and T helper cells [PMID: 10601351, PMID: 9500790]. Chemokines and their receptors can also be subclassified into homeostatic leukocyte homing molecules (CXCR4, CXCR5, CCR7, CCR9) versus inflammatory/inducible molecules (CXCR1, CXCR2, CXCR3, CCR1-6, CX3CR1).

The CXC chemokine receptors are a subfamily of chemokine receptors that specifically bind and respond to cytokines of the CXC chemokine family. There are currently seven known CXC chemokine receptors in mammals, CXCR1 through to CXCR7.

This entry represents CXC chemokine receptor 4 (CXCR4), also known as fusin, which is a specific receptor for a CXCL12 (or SDF1). CXCR4 has a wide cellular distribution, with expression on most immature and mature hematopoietic cell types [PMID: 9261420, PMID: 10985313, PMID: 12055238, PMID: 11154210, PMID: 11435493]. In addition, CXCR4 can also be found on vascular endothelial cells and neuronal/nerve cells [PMID: 9461627]. Upon binding to CXCR4, CXCL12 causes mobilisation of intracellular calcium and chemotaxis [PMID: 11876757, PMID: 12370187, PMID: 10525044]. CXCL12 is known to be important in hematopoietic stem cell homing to the bone marrow and in hematopoietic stem cell quiescence. CXCR4 has a rather broad activity, and has been linked to cardiac, cerebellar gastric vasculature development [PMID: 9634238, PMID: 11983855] and to hematopoiesis [PMID: 18378795]. It is also one of several chemokine receptors that HIV can use to infect CD4+ T cells [PMID: 9353123]. While the expression of CXCR4 is low or absent in many healthy tissues, it has been shown in over twenty three types of cancer, including breast, ovarian, melanoma, and prostate cancer [PMID: 20839032, PMID: 15229479].

Until recently, CXCL12 and CXCR4 were believed to be a relatively "monogamous" ligand-receptor pair, however there is evidence that ubiquitin is also a natural ligand of CXCR4 [PMID: 20228059]. Ubiquitin is anti-inflammatory immune modulator and endogenous opponent of proinflammatory damage associated molecular pattern molecules [PMID: 20689098], and it is thought that this interaction is through CXCR4 mediated signalling pathways.

GO terms

Biological Process

GO:0007186 G-protein coupled receptor signaling pathway
GO:0006935 chemotaxis
GO:0042119 neutrophil activation

Molecular Function

GO:0016494 C-X-C chemokine receptor activity

Cellular Component

GO:0016021 integral component of membrane

Contributing signatures

Signatures from InterPro member databases are used to construct an entry.
PANTHER
PRINTS