The Chemokine receptor CXCR4 is a 352 amino acid rhodopsin-like GPCR and selectively binds the CXC chemokine Stromal Cell-Derived Factor 1 (SDF-1) also known as CXCL12. Classically, two alternatively spliced isoforms of SDF have been identified. SDF-1Alpha is an 89 amino acid protein that is the predominantly expressed form of SDF-1 while SDF-1Beta contains a four amino acid extension at the carboxyl terminus. Recently, an additional four splice variants that contain 30 (SDF-1Gamma), 31 (SDF-1Delta), 1 (SDF-1Epsilon), and 51 (SDF-1phi) amino acid extensions at the carboxyl terminus compared to SDF-1Alpha have been identified (Ref.1).
Down-regulation of the CXCR4 receptor is initiated by phosphorylation of its cytoplasmic tail. Subsequent to the binding of arrestin to the COOH terminus of CXCR4, the receptor is internalized through endocytosis. Degradation of CXCR4 occurs in the lysosome. The CXCR4¡¤CXCR7 heterodimer complex recruits Beta-arrestin, resulting in preferential activation of Beta-arrestin-linked signaling pathways over canonical G protein pathways, including ERK1/2, p38 MAPK, and SAPK. Stimulation of other G-protein coupled receptors may also down-regulate CXCR4 signaling through a process called heterologous desensitization (Ref. 3 and 4). References 1.Regulation of CXCR4 signaling. Busillo JM, Benovic JL. Biochim Biophys Acta. 2007 Apr;1768(4):952-63. Epub 2006 Nov 10. Review. 2.Translating an Antagonist of Chemokine Receptor CXCR4: from bench to bedside. Wong D, Korz W. Clin Cancer Res. 2008 Dec 15;14(24):7975-80. doi: 10.1158/1078-0432.CCR-07-4846. Review. 3.Chemokine coreceptor signaling in HIV-1 infection and pathogenesis. Wu Y, Yoder A. PLoS Pathog. 2009 Dec;5(12):e1000520. doi: 10.1371/journal.ppat.1000520. Epub 2009 Dec 24. Review. 4.CXCR7/CXCR4 heterodimer constitutively recruits beta-arrestin to enhance cell migration. D¨¦caillot FM, Kazmi MA, Lin Y, Ray-Saha S, Sakmar TP, Sachdev P. J Biol Chem. 2011 Sep 16;286(37):32188-97. doi: 10.1074/jbc.M111.277038. Epub 2011 Jul 5. 5.CCR5/CD4/CXCR4 oligomerization prevents HIV-1 gp120IIIB binding to the cell surface. Mart¨ªnez-Muñoz L, Barroso R, Dyrhaug SY, Navarro G, Lucas P, Soriano SF, Vega B, Costas C, Muñoz-Fern¨¢ndez MÁ, Santiago C, Rodr¨ªguez Frade JM, Franco R, Mellado M. Proc Natl Acad Sci U S A. 2014 May 13;111(19):E1960-9. doi: 10.1073/pnas.1322887111. Epub 2014 Apr 28 6.HIV and the chemokine system: 10 years later. Lusso P. EMBO J. 2006 Feb 8;25(3):447-56. Epub 2006 Jan 26. Review. 7.CXCL12 (SDF-1)/CXCR4 pathway in cancer. Teicher BA, Fricker SP. Clin Cancer Res. 2010 Jun 1;16(11):2927-31. doi: 10.1158/1078-0432.CCR-09-2329. Epub 2010 May 18. Review.
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