CXCR4

• OMIM: 162 643
• UniProt: P61073
• MGI: 109563

CXCR4 (short for CXC motif chemokine receptor 4, also Stromal cell-derived factor 1 receptor ( SDF -1 receptor ), fusin, Leukocyte -derived seven transmembrane domain receptor ( LESTR ), CD184 ) is a receptor protein of the family of chemokine receptors. CXCR4 is found in many cells of the hematopoietic system and is especially expressed by many stem cells and tumor cells. This receptor is activated by the chemokine CXCL12, its only known ligand. CXCR4 plays a key role in the mobilization and targeted migration of stem cells in their memory (eg, fetal liver, bone marrow) or their places of use in the formation of organs ( organogenesis ) and the organ and wound healing. Pathophysiologically CXCR4 is involved in the growth and metastatic spread of tumors, as well as inflammatory processes. In addition, the primary CXCR4 co - receptor for T- cell -use (T -tropic ) HIV viruses.

• 3.1 Stem cell mobilization and anchoring
• 3.2 inflammation
• 3.3 cancer
• 3.4 HIV

Occurrence

Compared with other chemokine receptors CXCR4 shows a wide distribution within the organism. This receptor can be detected in the hematopoietic system in neutrophils, monocytes, T- lymphocytes, B- lymphocytes, pre-B cells, dendritic cells, and macrophages. Particularly characteristic is the expression of CXCR4 on CD34-positive progenitor cells. In addition, CXCR4 is formed by cells of the blood vessel endothelium of the central nervous system and the gastrointestinal tract. The majority of tumors are CXCR4 positive.

Biochemistry

Structure

CXCR4 is a transmembrane protein is selected from the group of G protein- coupled receptor encoded by a gene on the chromosome 2 gene locus q21. There are two different gene products are known which are caused by alternative splicing. The primary product of protein has a molecular mass of about 40 kDa and is subject to the following further modifications, such as glycosylation and sulphation. Recent findings pointing out that CXCR4 is present in dimeric or oligomeric form. These complexes also other receptors may be involved ( heterodimers or oligomers ).

Mutations

For CXCR4 mutations are described, which are manifested in a change in the receptor properties. Mutations of the DNA coding sequence at positions 1000 or 1013 of the CXCR4 gene leads to a shortened CXCR4 protein, the major parts of the intracellular C-terminus of the receptor is missing. By the absence of the C -terminus of the CXCR4 to lose the ability of the self-regulation by internalization following activation. The receptor can thus be dauerstimuliert. This rare mutation is considered as a possible cause of WHIM syndrome. Naturally-occurring receptor - inactivating mutations, such as described, for example, the chemokine receptor CCR5, are not known for CXCR4.

Receptor activation

CXCR4 is activated by its ligand CXCL12, whereby the receptor starts an intracellular signal transduction cascade. The binding and activation of CXCL12 to CXCR4 is assumed to be two-step process. In a first step CXCL12 binds to the extracellular N-terminus of the receptor. Then, the N -terminal end of the chemokine in the binding pocket of CXCR4, which lies within the transmembrane domains of the receptor, dive in and activate it.

Function

Stem cell mobilization and anchoring

The main function of CXCR4 is to control the migration of stem cells to sources of CXCL12, such as bone marrow, lung and liver. Connected thereto CXCR4 plays a crucial role in the attachment of stem cells to their locations and organogenesis. Knockout mice lacking CXCR4 or its ligand CXCL12 are not viable due to severe organ damage. After birth CXCR4 plays an important role in angiogenesis, wound healing and in the repair of organs.

Inflammation

Increased synthesis of CXCL12 in inflamed tissues and chemotactic effect on CXCR4 expressing lymphocytes is contacted with a role in inflammatory diseases in combination.

Cancer

Because the great majority of tumors express CXCR4, CXCL12 is a chemotactic effect on most tumor cells. This chemotactic effect is one of the main causes for the formation of metastases, which relate in particular to places with high CXCL12 production rate, especially bone marrow, lung and liver. Moreover, the CXCR4 CXCL12 - axis through a promotion of angiogenesis is also involved in tumor growth.

HIV

CXCR4 chemokine receptor CCR5 is next to the main co-receptor for docking and entry of HIV into human cells. For the endogenous CXCR4 agonist CXCL12 an inhibitory effect could be detected in the HI virus. This is attributed to a CXCL12 -induced internalization of CXCR4.

Pharmacology

Thanks to its role as an HIV co-receptor and its possible involvement in the formation and / or spread of cancer and inflammatory diseases is CXCR4 an attractive target for the development of new drugs. In the early 1990s succeeded thanks to a screening for HIV -inhibiting substances, the development of selective CXCR4 antagonists and HIV blocker plerixafor ( AMD3100 ) before CXCR4 could be identified and characterized. Plerixafor is now approved as a drug for release of stem cells into the bloodstream and subsequent autologous stem cell transplantation. Further developments led to substances with a better bioavailability (eg AMD070 ). Regardless led the elucidation of the pharmacological action of polyphemusin II of horseshoe crabs to the development of selective peptidic CXCR4 antagonist. However, these are not yet used therapeutically.