Posttranslational modifications of CXCR4: implications in cancer metastasis

Xiyun Deng, Juan Xu, Guangchun He, Yongguang Tao, Tao Yang, Xiaoning Peng, Ya Cao


CXCR4, the most widely expressed chemokine receptor in solid malignancies, has been implicated in cancer metastasis. However, how the activity of CXCR4 is regulated during carcinogenesis especially at the metastatic stage remains largely unknown. As with other G protein-coupled receptors, CXCR4 is subjected to posttranslational medications such as phosphorylation, ubiquitination, glycosylation, and sulfation. These posttranslational modifications contribute significantly to the heterogeneity of CXCR4 in terms of intracellular location, signaling, and functionality. We have shown that the difference in the sulfation level of CXCR4 is responsible for, if not all, the difference in the activities of CXCR4 between the highly metastatic and non-metastatic nasopharyngeal carcinoma (NPC) cell lines. Molecular mechanistic studies revealed that the Epstein-Barr virus-encoded oncoprotein LMP1 induces the expression of tyrosylprotein sulfotransferase 1 (TPST-1) through nuclear translocation of the epidermal growth factor receptor. This LMP1-regulated TPST-1 expression accounts for tyrosine sulfation of CXCR4 and is associated with the metastatic phenotype of NPC cell lines. Finally, in NPC patient specimens, there was a positive correlation between the expression of LMP1 and TPST-1 and the metastatic potential of NPC. Our findings provide the first evidence that the posttranslational modification of a chemokine receptor plays a role in cancer metastatic progression. Understanding the role of posttranslational modifications of chemokine receptors in cancer biology may provide new insights for developing attractive therapeutic targets in cancer therapy.

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Singh R, Lillard JW, Jr., Singh S. Chemokines: key players in cancer progression and metastasis. Front Biosci (Schol Ed) 2011;3:1569-1582.

Vinader V, Afarinkia K. The emerging role of CXC chemokines and their receptors in cancer. Future Med Chem 2012;4:853-867.


Ransohoff RM. Chemokines and chemokine receptors: standing at the crossroads of immunobiology and neurobiology. Immunity 2009;31:711-721.

PMid:19836265 PMCid:PMC2787682

Miyazaki H, Takabe K, Yeudall WA. Chemokines, chemokine receptors and the gastrointestinal system. World J Gastroenterol 2013;19:2847-2863.

PMid:23704819 PMCid:PMC3660811

Richmond A. Chemokine modulation of the tumor microenvironment. Pigment Cell Melanoma Res 2010;23:312-313.

PMid:20415714 PMCid:PMC3140344

Keeley EC, Mehrad B, Strieter RM. CXC chemokines in cancer angiogenesis and metastases. Adv Cancer Res 2010;106:91-111.

Berger EA, Murphy PM, Farber JM. Chemokine receptors as HIV-1 coreceptors: roles in viral entry, tropism, and disease. Annu Rev Immunol 1999;17:657-700.


Zlotnik A. Chemokines and cancer. Int J Cancer 2006;119:2026-2029.


Sun X, Cheng G, Hao M, Zheng J, Zhou X, Zhang J, et al. CXCL12 / CXCR4 / CXCR7 chemokine axis and cancer progression. Cancer Metastasis Rev 2010;29:709-722.

PMid:20839032 PMCid:PMC3175097

Muller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME, et al. Involvement of chemokine receptors in breast cancer metastasis. Nature 2001;410:50-56.


Furusato B, Mohamed A, Uhlen M, Rhim JS. CXCR4 and cancer. Pathol Int 2010;60:497-505.


Liekens S, Schols D, Hatse S. CXCL12-CXCR4 axis in angiogenesis, metastasis and stem cell mobilization. Curr Pharm Des 2010;16:3903-3920.


Toth PT, Ren D, Miller RJ. Regulation of CXCR4 receptor dimerization by the chemokine SDF-1alpha and the HIV-1 coat protein gp120: a fluorescence resonance energy transfer (FRET) study. J Pharmacol Exp Ther 2004;310:8-17.


Babcock GJ, Farzan M, Sodroski J. Ligand-independent dimerization of CXCR4, a principal HIV-1 coreceptor. J Biol Chem 2003;278:3378-3385.


Rodriguez-Frade JM, del Real G, Serrano A, Hernanz-Falcon P, Soriano SF, Vila-Coro AJ, et al. Blocking HIV-1 infection via CCR5 and CXCR4 receptors by acting in trans on the CCR2 chemokine receptor. EMBO J 2004;23:66-76.

PMid:14685276 PMCid:PMC1271658

Sohy D, Parmentier M, Springael JY. Allosteric transinhibition by specific antagonists in CCR2/CXCR4 heterodimers. J Biol Chem 2007;282:30062-30069.


Sohy D, Yano H, de Nadai P, Urizar E, Guillabert A, Javitch JA, et al. Hetero-oligomerization of CCR2, CCR5, and CXCR4 and the protean effects of "selective" antagonists. J Biol Chem 2009;284:31270-31279.

PMid:19758998 PMCid:PMC2781525

Levoye A, Balabanian K, Baleux F, Bachelerie F, Lagane B. CXCR7 heterodimerizes with CXCR4 and regulates CXCL12-mediated G protein signaling. Blood 2009;113: 6085-6093.


Basmaciogullari S, Pacheco B, Bour S, Sodroski J. Specific interaction of CXCR4 with CD4 and CD8alpha: functional analysis of the CD4/CXCR4 interaction in the context of HIV-1 envelope glycoprotein-mediated membrane fusion. Virology 2006;353:52-67.


Raman D, Sobolik-Delmaire T, Richmond A. Chemokines in health and disease. Exp Cell Res 2011;317:575-589.

PMid:21223965 PMCid:PMC3063402

Haribabu B, Richardson RM, Fisher I, Sozzani S, Peiper SC, Horuk R, et al. Regulation of human chemokine receptors CXCR4. Role of phosphorylation in desensitization and internalization. J Biol Chem 1997;272: 28726-28731.


Signoret N, Oldridge J, Pelchen-Matthews A, Klasse PJ, Tran T, Brass LF, et al. Phorbol esters and SDF-1 induce rapid endocytosis and down modulation of the chemokine receptor CXCR4. J Cell Biol 1997;139:651-664.

PMid:9348282 PMCid:PMC2141706

Woerner BM, Warrington NM, Kung AL, Perry A, Rubin JB. Widespread CXCR4 activation in astrocytomas revealed by phospho-CXCR4-specific antibodies. Cancer Res 2005;65:11392-11399.


Orsini MJ, Parent JL, Mundell SJ, Marchese A, Benovic JL. Trafficking of the HIV coreceptor CXCR4. Role of arrestins and identification of residues in the c-terminal tail that mediate receptor internalization. J Biol Chem 1999;274:31076-31086.


Marchese A, Benovic JL. Agonist-promoted ubiquitination of the G protein-coupled receptor CXCR4 mediates lysosomal sorting. J Biol Chem 2001;276:45509-45512.


Marchese A, Chen C, Kim YM, Benovic JL. The ins and outs of G protein-coupled receptor trafficking. Trends Biochem Sci 2003;28:369-376.

Marchese A, Raiborg C, Santini F, Keen JH, Stenmark H, Benovic JL. The E3 ubiquitin ligase AIP4 mediates ubiquitination and sorting of the G protein-coupled receptor CXCR4. Dev Cell 2003;5:709-722.

Berson JF, Long D, Doranz BJ, Rucker J, Jirik FR, Doms RW. A seven-transmembrane domain receptor involved in fusion and entry of T-cell-tropic human immunodeficiency virus type 1 strains. J Virol 1996;70:6288-6295.

PMid:8709256 PMCid:PMC190654

Chabot DJ, Chen H, Dimitrov DS, Broder CC. N-linked glycosylation of CXCR4 masks coreceptor function for CCR5-dependent human immunodeficiency virus type 1 isolates. J Virol 2000;74:4404-4413.

PMid:10756055 PMCid:PMC111957

Wang J, Babcock GJ, Choe H, Farzan M, Sodroski J, Gabuzda D. N-linked glycosylation in the CXCR4 N-terminus inhibits binding to HIV-1 envelope glycoproteins. Virology 2004;324:140-150.


Zhou H, Tai HH. Characterization of recombinant human CXCR4 in insect cells: role of extracellular domains and N-glycosylation in ligand binding. Arch Biochem Biophys 1999;369:267-276.


Huttner WB. Sulphation of tyrosine residues-a widespread modification of proteins. Nature 1982;299:273-276.


Baeuerle PA, Huttner WB. Tyrosine sulfation is a trans-Golgi-specific protein modification. J Cell Biol 1987;105: 2655-2664.

Seibert C, Sakmar TP. Toward a framework for sulfoproteomics: Synthesis and characterization of sulfotyrosine-containing peptides. Biopolymers 2008;90: 459-477.


Ouyang Y, Lane WS, Moore KL. Tyrosylprotein sulfotransferase: purification and molecular cloning of an enzyme that catalyzes tyrosine O-sulfation, a common posttranslational modification of eukaryotic proteins. Proc Natl Acad Sci U S A 1998;95:2896-2901.

PMid:9501187 PMCid:PMC19666

Beisswanger R, Corbeil D, Vannier C, Thiele C, Dohrmann U, Kellner R, et al. Existence of distinct tyrosylprotein sulfotransferase genes: molecular characterization of tyrosylprotein sulfotransferase-2. Proc Natl Acad Sci U S A 1998;95:11134-11139.

PMid:9736702 PMCid:PMC21608

Moore KL. The biology and enzymology of protein tyrosine O-sulfation. J Biol Chem 2003;278:24243-24246.


Farzan M, Babcock GJ, Vasilieva N, Wright PL, Kiprilov E, Mirzabekov T, et al. The role of post-translational modifications of the CXCR4 amino terminus in stromal-derived factor 1 alpha association and HIV-1 entry. J Biol Chem 2002;277:29484-29489.


Veldkamp CT, Seibert C, Peterson FC, Sakmar TP, Volkman BF. Recognition of a CXCR4 sulfotyrosine by the chemokine stromal cell-derived factor-1alpha (SDF-1alpha/CXCL12). J Mol Biol 2006;359:1400-1409.

PMid:16725153 PMCid:PMC2670582

Hu J, Deng X, Bian X, Li G, Tong Y, Li Y, et al. The expression of functional chemokine receptor CXCR4 is associated with the metastatic potential of human nasopharyngeal carcinoma. Clin Cancer Res 2005;11: 4658-4665.


Tao Y, Song X, Deng X, Xie D, Lee LM, Liu Y, et al. Nuclear accumulation of epidermal growth factor receptor and acceleration of G1/S stage by Epstein-Barr-encoded oncoprotein latent membrane protein 1. Exp Cell Res 2005;303:240-251.


Xu J, Deng X, Tang M, Li L, Xiao L, Yang L, et al. Tyrosylprotein sulfotransferase-1 and tyrosine sulfation of chemokine receptor 4 are induced by Epstein-Barr virus encoded latent membrane protein 1 and associated with the metastatic potential of human nasopharyngeal carcinoma. PLoS One 2013;8:e56114.

PMid:23472069 PMCid:PMC3589389



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