{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T12:02:59Z","timestamp":1790251379689,"version":"4.1.0"},"reference-count":81,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2020,8,8]],"date-time":"2020-08-08T00:00:00Z","timestamp":1596844800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Italian Ministery of Health","award":["GR-2013-02356521"],"award-info":[{"award-number":["GR-2013-02356521"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Given its pleiotropic functions, including its prominent role in inflammation, immune responses and cancer, the C-X-C chemokine receptor type 4 (CXCR4) has gained significant attention in recent years and has become a relevant target in drug development. Although the signaling properties of CXCR4 have been extensively studied, several aspects deserve deeper investigations. Mutations in the C-term tail of the CXCR4 gene cause WHIM syndrome, a rare congenital immunodeficiency associated by chronic leukopenia. Similar mutations have also been recently identified in 30% of patients affected by Waldenstrom\u2019s macroglobulinaemia, a B-cell neoplasia with bone marrow accumulation of malignant cells. An ample body of work has been generated to define the impact of WHIM mutations on CXCR4 signaling properties and evaluate their role on pathogenesis, diagnosis, and response to therapy, although the identity of disease-causing signaling pathways and their relevance for disease development in different genetic variants are still open questions. This review discusses the current knowledge on biochemical properties of CXCR4 mutations to identify their prototypic signaling profile potentially useful to highlighting novel opportunities for therapeutic intervention.<\/jats:p>","DOI":"10.3390\/ijms21165696","type":"journal-article","created":{"date-parts":[[2020,8,10]],"date-time":"2020-08-10T05:07:23Z","timestamp":1597036043000},"page":"5696","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Aberrant CXCR4 Signaling at Crossroad of WHIM Syndrome and Waldenstrom\u2019s Macroglobulinemia"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8055-1686","authenticated-orcid":false,"given":"Samantha","family":"Milanesi","sequence":"first","affiliation":[{"name":"Humanitas Clinical and Research Center-IRCCS, Via Manzoni 56, I-20089 Rozzano (Milan), Italy"},{"name":"Department of Medical Biotechnologies and Translational Medicine, University of Milan, Via Fratelli Cervi, I-20090 Segrate (Milan), Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3077-590X","authenticated-orcid":false,"given":"Massimo","family":"Locati","sequence":"additional","affiliation":[{"name":"Humanitas Clinical and Research Center-IRCCS, Via Manzoni 56, I-20089 Rozzano (Milan), Italy"},{"name":"Department of Medical Biotechnologies and Translational Medicine, University of Milan, Via Fratelli Cervi, I-20090 Segrate (Milan), Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1157-8249","authenticated-orcid":false,"given":"Elena Monica","family":"Borroni","sequence":"additional","affiliation":[{"name":"Humanitas Clinical and Research Center-IRCCS, Via Manzoni 56, I-20089 Rozzano (Milan), Italy"},{"name":"Department of Medical Biotechnologies and Translational Medicine, University of Milan, Via Fratelli Cervi, I-20090 Segrate (Milan), Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,8,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1016\/S0021-9258(17)42339-8","article-title":"Cloning of a human seven-transmembrane domain receptor, LESTR, that is highly expressed in leukocytes","volume":"269","author":"Loetscher","year":"1994","journal-title":"J. Biol. Chem."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"878","DOI":"10.1016\/j.tim.2019.06.002","article-title":"Molecular Mechanism of HIV-1 Entry","volume":"27","author":"Chen","year":"2019","journal-title":"Trends Microbiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/j.biocel.2017.12.018","article-title":"The good and bad faces of the CXCR4 chemokine receptor","volume":"95","author":"Teixido","year":"2018","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"429","DOI":"10.3389\/fimmu.2015.00429","article-title":"Diversity and Inter-Connections in the CXCR4 Chemokine Receptor\/Ligand Family: Molecular Perspectives","volume":"6","author":"Pawig","year":"2015","journal-title":"Front. Immunol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1111\/imr.12719","article-title":"WHIM syndrome: Immunopathogenesis, treatment and cure strategies","volume":"287","author":"McDermott","year":"2019","journal-title":"Immunol. Rev."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1007\/978-3-319-40320-5_16","article-title":"Waldenstrom Macroglobulinemia: Genomic Aberrations and Treatment","volume":"169","author":"Kapoor","year":"2016","journal-title":"Cancer Treat. Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1016\/j.imlet.2016.06.006","article-title":"CXCR4 signaling in health and disease","volume":"177","author":"Pozzobon","year":"2016","journal-title":"Immunol. Lett."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1188","DOI":"10.1002\/med.21464","article-title":"Harnessing CXCR4 antagonists in stem cell mobilization, HIV infection, ischemic diseases, and oncology","volume":"38","author":"Tsou","year":"2018","journal-title":"Med. Res. Rev."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Scala, S., D\u2019Alterio, C., Milanesi, S., Castagna, A., Carriero, R., Farina, F.M., Locati, M., and Borroni, E.M. (2020). New Insights on the Emerging Genomic Landscape of CXCR4 in Cancer: A Lesson from WHIM. Vaccines, 8.","DOI":"10.3390\/vaccines8020164"},{"key":"ref_10","first-page":"253","article-title":"Toward third-generation aptamers: Spiegelmers and their therapeutic prospects","volume":"6","author":"Vater","year":"2003","journal-title":"Curr. Opin. Drug Discov. Dev."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1032","DOI":"10.1182\/blood-2013-03-493924","article-title":"The Spiegelmer NOX-A12, a novel CXCL12 inhibitor, interferes with chronic lymphocytic leukemia cell motility and causes chemosensitization","volume":"123","author":"Hoellenriegel","year":"2014","journal-title":"Blood"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2053","DOI":"10.3324\/haematol.2018.205930","article-title":"Olaptesed pegol (NOX-A12) with bendamustine and rituximab: A phase IIa study in patients with relapsed\/refractory chronic lymphocytic leukemia","volume":"104","author":"Steurer","year":"2019","journal-title":"Haematologica"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"109973","DOI":"10.18632\/oncotarget.22409","article-title":"Inhibition of SDF-1-induced migration of oncogene-driven myeloid leukemia by the L-RNA aptamer (Spiegelmer), NOX-A12, and potentiation of tyrosine kinase inhibition","volume":"8","author":"Weisberg","year":"2017","journal-title":"Oncotarget"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2391","DOI":"10.1002\/stem.2054","article-title":"Concise Review: CXCR4\/CXCL12 Signaling in Immature Hematopoiesis--Lessons From Pharmacological and Genetic Models","volume":"33","author":"Karpova","year":"2015","journal-title":"Stem Cells"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1056\/NEJM196404022701402","article-title":"\u201cMyelokathexis\u201d\u2014A New Form of Chronic Granulocytopenia. Report of a Case","volume":"270","author":"Zuelzer","year":"1964","journal-title":"N. Engl. J. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1038\/ng1149","article-title":"Mutations in the chemokine receptor gene CXCR4 are associated with WHIM syndrome, a combined immunodeficiency disease","volume":"34","author":"Hernandez","year":"2003","journal-title":"Nat. Genet."},{"key":"ref_17","first-page":"2040206619829382","article-title":"Mozobil(R) (Plerixafor, AMD3100), 10 years after its approval by the US Food and Drug Administration","volume":"27","year":"2019","journal-title":"Antivir. Chem. Chemother."},{"key":"ref_18","first-page":"276","article-title":"AMD3100\/CXCR4 Inhibitor","volume":"6","year":"2015","journal-title":"Front. Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"4278","DOI":"10.1158\/1078-0432.CCR-14-0914","article-title":"Molecular Pathways: Targeting the CXCR4-CXCL12 Axis\u2014Untapped Potential in the Tumor Microenvironment","volume":"21","author":"Scala","year":"2015","journal-title":"Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/bs.ai.2017.02.001","article-title":"A Chemoattractant-Guided Walk Through Lymphopoiesis: From Hematopoietic Stem Cells to Mature B Lymphocytes","volume":"134","author":"Lim","year":"2017","journal-title":"Adv. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1159\/000497430","article-title":"C-X-C Chemokine Receptor 4 in Diffuse Large B Cell Lymphoma: Achievements and Challenges","volume":"142","author":"Du","year":"2019","journal-title":"Acta Haematol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1182\/blood-2016-07-729954","article-title":"Recurrent somatic mutations affecting B-cell receptor signaling pathway genes in follicular lymphoma","volume":"129","author":"Krysiak","year":"2017","journal-title":"Blood"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1637","DOI":"10.1182\/blood-2013-09-525808","article-title":"The genomic landscape of Waldenstrom macroglobulinemia is characterized by highly recurring MYD88 and WHIM-like CXCR4 mutations, and small somatic deletions associated with B-cell lymphomagenesis","volume":"123","author":"Hunter","year":"2014","journal-title":"Blood"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1097\/MOH.0000000000000254","article-title":"Oncogenic Notch signaling in T-cell and B-cell lymphoproliferative disorders","volume":"23","author":"Chiang","year":"2016","journal-title":"Curr. Opin. Hematol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1016\/j.ccell.2015.05.003","article-title":"CXCR4 Is Required for Leukemia-Initiating Cell Activity in T Cell Acute Lymphoblastic Leukemia","volume":"27","author":"Passaro","year":"2015","journal-title":"Cancer Cell"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e565","DOI":"10.1038\/bcj.2017.40","article-title":"Waldenstrom macroglobulinemia cells devoid of BTK(C481S) or CXCR4(WHIM-like) mutations acquire resistance to ibrutinib through upregulation of Bcl-2 and AKT resulting in vulnerability towards venetoclax or MK2206 treatment","volume":"7","author":"Paulus","year":"2017","journal-title":"Blood Cancer J."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1111\/bjh.16088","article-title":"CXCR4 mutation subtypes impact response and survival outcomes in patients with Waldenstrom macroglobulinaemia treated with ibrutinib","volume":"187","author":"Castillo","year":"2019","journal-title":"Br. J. Haematol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1080\/17474086.2019.1649132","article-title":"CXCR4 mutations affect presentation and outcomes in patients with Waldenstrom macroglobulinemia: A systematic review","volume":"12","author":"Castillo","year":"2019","journal-title":"Expert Rev. Hematol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"994","DOI":"10.1200\/JCO.2016.71.0814","article-title":"Genomics, Signaling, and Treatment of Waldenstrom Macroglobulinemia","volume":"35","author":"Hunter","year":"2017","journal-title":"J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1007\/s12032-015-0705-9","article-title":"Are there any new insights for G-CSF and\/or AMD3100 in chemotherapy of haematological malignants?","volume":"32","author":"Shen","year":"2015","journal-title":"Med. Oncol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.bcmd.2016.03.009","article-title":"AMD3100 and G-CSF disrupt the cross-talk between leukemia cells and the endosteal niche and enhance their sensitivity to chemotherapeutic drugs in biomimetic polystyrene scaffolds","volume":"59","author":"Shen","year":"2016","journal-title":"Blood Cells Mol. Dis."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1182\/blood-2011-12-395608","article-title":"WHIM syndrome caused by a single amino acid substitution in the carboxy-tail of chemokine receptor CXCR4","volume":"120","author":"Liu","year":"2012","journal-title":"Blood"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2449","DOI":"10.1182\/blood-2004-06-2289","article-title":"WHIM syndromes with different genetic anomalies are accounted for by impaired CXCR4 desensitization to CXCL12","volume":"105","author":"Balabanian","year":"2005","journal-title":"Blood"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1480","DOI":"10.1158\/1078-0432.CCR-15-0646","article-title":"Genomic Landscape of CXCR4 Mutations in Waldenstrom Macroglobulinemia","volume":"22","author":"Poulain","year":"2016","journal-title":"Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"794","DOI":"10.1124\/mol.118.115360","article-title":"CXCR4\/ACKR3 Phosphorylation and Recruitment of Interacting Proteins: Key Mechanisms Regulating Their Functional Status","volume":"96","author":"Fumagalli","year":"2019","journal-title":"Mol. Pharmacol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"952","DOI":"10.1016\/j.bbamem.2006.11.002","article-title":"Regulation of CXCR4 signaling","volume":"1768","author":"Busillo","year":"2007","journal-title":"Biochim. Et Biophys. Acta"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2749","DOI":"10.1016\/j.febslet.2009.07.058","article-title":"A functional heteromeric MIF receptor formed by CD74 and CXCR4","volume":"583","author":"Schwartz","year":"2009","journal-title":"FEBS Lett."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1825","DOI":"10.1182\/blood-2006-05-023028","article-title":"Endolyn (CD164) modulates the CXCL12-mediated migration of umbilical cord blood CD133+ cells","volume":"109","author":"Forde","year":"2007","journal-title":"Blood"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1146\/annurev.physiol.69.022405.154749","article-title":"Beta-arrestins and cell signaling","volume":"69","author":"DeWire","year":"2007","journal-title":"Annu. Rev. Physiol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1146\/annurev.physiol.69.022405.154712","article-title":"Regulation of receptor trafficking by GRKs and arrestins","volume":"69","author":"Moore","year":"2007","journal-title":"Annu. Rev. Physiol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1116","DOI":"10.1182\/blood-2014-09-601807","article-title":"Filamin A interaction with the CXCR4 third intracellular loop regulates endocytosis and signaling of WT and WHIM-like receptors","volume":"125","author":"Fischer","year":"2015","journal-title":"Blood"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1324","DOI":"10.1091\/mbc.e08-03-0308","article-title":"The E3 ubiquitin ligase atrophin interacting protein 4 binds directly to the chemokine receptor CXCR4 via a novel WW domain-mediated interaction","volume":"20","author":"Bhandari","year":"2009","journal-title":"Mol. Biol. Cell"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1160","DOI":"10.1242\/jcs.064238","article-title":"F-actin-binding protein drebrin regulates CXCR4 recruitment to the immune synapse","volume":"123","author":"Cabrero","year":"2010","journal-title":"J. Cell Sci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1016\/j.bbrc.2017.01.087","article-title":"mDia2 and CXCL12\/CXCR4 chemokine signaling intersect to drive tumor cell amoeboid morphological transitions","volume":"484","author":"Wyse","year":"2017","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1016\/j.ccr.2011.04.016","article-title":"Receptor tyrosine kinases and TLR\/IL1Rs unexpectedly activate myeloid cell PI3kgamma, a single convergent point promoting tumor inflammation and progression","volume":"19","author":"Schmid","year":"2011","journal-title":"Cancer Cell"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"5410","DOI":"10.4049\/jimmunol.169.10.5410","article-title":"Cutting edge: Association of the motor protein nonmuscle myosin heavy chain-IIA with the C terminus of the chemokine receptor CXCR4 in T lymphocytes","volume":"169","author":"Rey","year":"2002","journal-title":"J Immunol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1007\/s10875-019-00665-w","article-title":"WHIM Syndrome: From Pathogenesis Towards Personalized Medicine and Cure","volume":"39","author":"Heusinkveld","year":"2019","journal-title":"J. Clin. Immunol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1067\/mjd.2001.111337","article-title":"B-cell lymphoma in a patient with WHIM syndrome","volume":"44","author":"Chae","year":"2001","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1007\/s00277-002-0489-9","article-title":"Epstein-Barr virus-associated T-lymphoproliferative disease with hemophagocytic syndrome, followed by fatal intestinal B lymphoma in a young adult female with WHIM syndrome. Warts, hypogammaglobulinemia, infections, and myelokathexis","volume":"81","author":"Imashuku","year":"2002","journal-title":"Ann. Hematol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1366","DOI":"10.1016\/j.exphem.2007.05.022","article-title":"Establishment of BCWM.1 cell line for Waldenstrom\u2019s macroglobulinemia with productive in vivo engraftment in SCID-hu mice","volume":"35","author":"Ho","year":"2007","journal-title":"Exp. Hematol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"e190","DOI":"10.1182\/blood-2010-12-326868","article-title":"Establishment and characterization of a novel Waldenstrom macroglobulinemia cell line, MWCL-1","volume":"117","author":"Hodge","year":"2011","journal-title":"Blood"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2071","DOI":"10.1111\/j.1582-4934.2010.01210.x","article-title":"AMD3100 is a potent antagonist at CXCR4(R334X), a hyperfunctional mutant chemokine receptor and cause of WHIM syndrome","volume":"15","author":"McDermott","year":"2011","journal-title":"J. Cell. Mol. Med."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1016\/j.exphem.2005.01.001","article-title":"Enhanced function with decreased internalization of carboxy-terminus truncated CXCR4 responsible for WHIM syndrome","volume":"33","author":"Kawai","year":"2005","journal-title":"Exp. Hematol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1262","DOI":"10.3389\/fimmu.2019.01262","article-title":"Enhanced Bone Marrow Homing of Natural Killer Cells Following mRNA Transfection With Gain-of-Function Variant CXCR4(R334X)","volume":"10","author":"Levy","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"McCormick, P.J., Segarra, M., Gasperini, P., Gulino, A.V., and Tosato, G. (2009). Impaired recruitment of Grk6 and beta-Arrestin 2 causes delayed internalization and desensitization of a WHIM syndrome-associated CXCR4 mutant receptor. PLoS ONE, 4.","DOI":"10.1371\/journal.pone.0008102"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1182\/blood-2003-10-3532","article-title":"Altered leukocyte response to CXCL12 in patients with warts hypogammaglobulinemia, infections, myelokathexis (WHIM) syndrome","volume":"104","author":"Gulino","year":"2004","journal-title":"Blood"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1038\/leu.2014.187","article-title":"The WHIM-like CXCR4(S338X) somatic mutation activates AKT and ERK, and promotes resistance to ibrutinib and other agents used in the treatment of Waldenstrom\u2019s Macroglobulinemia","volume":"29","author":"Cao","year":"2015","journal-title":"Leukemia"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1111\/bjh.13200","article-title":"CXCR4 WHIM-like frameshift and nonsense mutations promote ibrutinib resistance but do not supplant MYD88(L265P)-directed survival signalling in Waldenstrom macroglobulinaemia cells","volume":"168","author":"Cao","year":"2015","journal-title":"Br. J. Haematol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"2800","DOI":"10.1182\/bloodadvances.2019000635","article-title":"CXCR4 (S338X) clonality is an important determinant of ibrutinib outcomes in patients with Waldenstrom macroglobulinemia","volume":"3","author":"Gustine","year":"2019","journal-title":"Blood Adv."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Castellani, F., Visentin, A., Campagnolo, M., Salvalaggio, A., Cacciavillani, M., Candiotto, C., Bertorelle, R., Trentin, L., and Briani, C. (2020). The Bruton tyrosine kinase inhibitor ibrutinib improves anti-MAG antibody polyneuropathy. Neurol. Neuroimmunol. Neuroinflamm., 7.","DOI":"10.1212\/NXI.0000000000000720"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1182\/blood-2007-07-102103","article-title":"CXCR4 dimerization and beta-arrestin-mediated signaling account for the enhanced chemotaxis to CXCL12 in WHIM syndrome","volume":"112","author":"Lagane","year":"2008","journal-title":"Blood"},{"key":"ref_62","first-page":"1074","article-title":"Leukocyte analysis from WHIM syndrome patients reveals a pivotal role for GRK3 in CXCR4 signaling","volume":"118","author":"Balabanian","year":"2008","journal-title":"J. Clin. Investig."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1007\/s10875-016-0276-3","article-title":"WHIM Syndrome Caused by Waldenstrom\u2019s Macroglobulinemia-Associated Mutation CXCR4 (L329fs)","volume":"36","author":"Liu","year":"2016","journal-title":"J. Clin. Immunol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"6996","DOI":"10.1093\/emboj\/16.23.6996","article-title":"Solution structure and basis for functional activity of stromal cell-derived factor-1; dissociation of CXCR4 activation from binding and inhibition of HIV-1","volume":"16","author":"Crump","year":"1997","journal-title":"EMBO J."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.bcp.2016.04.005","article-title":"The impact of RGS and other G-protein regulatory proteins on Galphai-mediated signaling in immunity","volume":"114","author":"Kehrl","year":"2016","journal-title":"Biochem. Pharmacol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1038\/nrm2299","article-title":"Heterotrimeric G protein activation by G-protein-coupled receptors","volume":"9","author":"Oldham","year":"2008","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"7805","DOI":"10.1074\/jbc.M109.091173","article-title":"Site-specific phosphorylation of CXCR4 is dynamically regulated by multiple kinases and results in differential modulation of CXCR4 signaling","volume":"285","author":"Busillo","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Mueller, W., Schutz, D., Nagel, F., Schulz, S., and Stumm, R. (2013). Hierarchical organization of multi-site phosphorylation at the CXCR4 C terminus. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0064975"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"2479","DOI":"10.1074\/jbc.275.4.2479","article-title":"beta-arrestin differentially regulates the chemokine receptor CXCR4-mediated signaling and receptor internalization, and this implicates multiple interaction sites between beta-arrestin and CXCR4","volume":"275","author":"Cheng","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1124\/mol.116.106468","article-title":"G Protein-Coupled Receptor Kinase 3 and Protein Kinase C Phosphorylate the Distal C-Terminal Tail of the Chemokine Receptor CXCR4 and Mediate Recruitment of beta-Arrestin","volume":"91","author":"Luo","year":"2017","journal-title":"Mol. Pharmacol."},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Yang, P., Hu, Y., and Zhou, Q. (2019). The CXCL12-CXCR4 signaling axis plays a key role in cancer metastasis and is a potential target for developing novel therapeutics against metastatic cancer. Curr. Med. Chem.","DOI":"10.2174\/0929867326666191113113110"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1146\/annurev-biophys-050511-102252","article-title":"Filamins in mechanosensing and signaling","volume":"41","author":"Razinia","year":"2012","journal-title":"Annu. Rev. Biophys."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1146\/annurev.pharmtox.42.091701.082314","article-title":"Dimerization: An emerging concept for G protein-coupled receptor ontogeny and function","volume":"42","author":"Angers","year":"2002","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Doijen, J., Van Loy, T., De Haes, W., Landuyt, B., Luyten, W., Schoofs, L., and Schols, D. (2017). Signaling properties of the human chemokine receptors CXCR4 and CXCR7 by cellular electric impedance measurements. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0185354"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"6085","DOI":"10.1182\/blood-2008-12-196618","article-title":"CXCR7 heterodimerizes with CXCR4 and regulates CXCL12-mediated G protein signaling","volume":"113","author":"Levoye","year":"2009","journal-title":"Blood"},{"key":"ref_76","first-page":"823","article-title":"Imaging chemokine receptor dimerization with firefly luciferase complementation","volume":"23","author":"Luker","year":"2009","journal-title":"Faseb J. Off. Publ. Fed. Am. Soc. Exp. Biol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"14759","DOI":"10.1073\/pnas.0702229104","article-title":"Disrupted cardiac development but normal hematopoiesis in mice deficient in the second CXCL12\/SDF-1 receptor, CXCR7","volume":"104","author":"Sierro","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"2497","DOI":"10.1093\/emboj\/20.10.2497","article-title":"Chemokine receptor homo- or heterodimerization activates distinct signaling pathways","volume":"20","author":"Mellado","year":"2001","journal-title":"EMBO J."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"282","DOI":"10.3389\/fimmu.2015.00282","article-title":"The Structure of a CXCR4:Chemokine Complex","volume":"6","author":"Handel","year":"2015","journal-title":"Front. Immunol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1066","DOI":"10.1126\/science.1194396","article-title":"Structures of the CXCR4 chemokine GPCR with small-molecule and cyclic peptide antagonists","volume":"330","author":"Wu","year":"2010","journal-title":"Science"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/j.molcel.2018.02.034","article-title":"Separating Actin-Dependent Chemokine Receptor Nanoclustering from Dimerization Indicates a Role for Clustering in CXCR4 Signaling and Function","volume":"70","author":"Barroso","year":"2018","journal-title":"Mol. Cell"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/16\/5696\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:58:19Z","timestamp":1760176699000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/16\/5696"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,8,8]]},"references-count":81,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2020,8]]}},"alternative-id":["ijms21165696"],"URL":"https:\/\/doi.org\/10.3390\/ijms21165696","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,8,8]]}}}