The chemokine receptor CXCR4 plays important roles in the immune and nervous systems. Abnormal expression of CXCR4 contributes to cancer and inflammatory and neurodegenerative disorders. Although ligand-dependent CXCR4 ubiquitination is known to accelerate CXCR4 degradation, little is known about counter mechanisms for receptor deubiquitination. CXCL12, a CXCR4 agonist, induces a time-dependent association of USP14 with CXCR4, or its C terminus, that is not mimicked by USP2A, USP4, or USP7, other members of the deubiquitination catalytic family. Co-localization of CXCR4 and USP14 also is time-dependent following CXCL12 stimulation. The physical interaction of CXCR4 and USP14 is paralleled by USP14-catalyzed deubiquitination of the receptor; knockdown of endogenous USP14 by RNA interference (RNAi) blocks CXCR4 deubiquitination, whereas overexpression of USP14 promotes CXCR4 deubiquitination. We also observed that ubiquitination of CXCR4 facilitated receptor degradation, whereas overexpression of USP14 or RNAi-induced knockdown of USP14 blocked CXCL12-mediated CXCR4 degradation. Most interestingly, CXCR4-mediated chemotactic cell migration was blocked by either overexpression or RNAi-mediated knockdown of USP14, implying that a CXCR4-ubiquitin cycle on the receptor, rather than a particular ubiquitinated state of the receptor, is critical for the ligand gradient sensing and directed motility required for chemokine-mediated chemotaxis. Our observation that a mutant of CXCR4, HA-3K/R CXCR4, which cannot be ubiquitinated and does not mediate a chemotactic response to CXCL12, indicates the importance of this covalent modification not only in marking receptors for degradation but also for permitting CXCR4-mediated signaling. Finally, the indistinguishable activation of ERK by wild typeor 3K/R-CXCR4 suggests that chemotaxis in response to CXCL12 may be independent of the ERK cascade. The chemokine receptor CXCR4 plays important roles in the immune and nervous systems. Abnormal expression of CXCR4 contributes to cancer and inflammatory and neurodegenerative disorders. Although ligand-dependent CXCR4 ubiquitination is known to accelerate CXCR4 degradation, little is known about counter mechanisms for receptor deubiquitination. CXCL12, a CXCR4 agonist, induces a time-dependent association of USP14 with CXCR4, or its C terminus, that is not mimicked by USP2A, USP4, or USP7, other members of the deubiquitination catalytic family. Co-localization of CXCR4 and USP14 also is time-dependent following CXCL12 stimulation. The physical interaction of CXCR4 and USP14 is paralleled by USP14-catalyzed deubiquitination of the receptor; knockdown of endogenous USP14 by RNA interference (RNAi) blocks CXCR4 deubiquitination, whereas overexpression of USP14 promotes CXCR4 deubiquitination. We also observed that ubiquitination of CXCR4 facilitated receptor degradation, whereas overexpression of USP14 or RNAi-induced knockdown of USP14 blocked CXCL12-mediated CXCR4 degradation. Most interestingly, CXCR4-mediated chemotactic cell migration was blocked by either overexpression or RNAi-mediated knockdown of USP14, implying that a CXCR4-ubiquitin cycle on the receptor, rather than a particular ubiquitinated state of the receptor, is critical for the ligand gradient sensing and directed motility required for chemokine-mediated chemotaxis. Our observation that a mutant of CXCR4, HA-3K/R CXCR4, which cannot be ubiquitinated and does not mediate a chemotactic response to CXCL12, indicates the importance of this covalent modification not only in marking receptors for degradation but also for permitting CXCR4-mediated signaling. Finally, the indistinguishable activation of ERK by wild typeor 3K/R-CXCR4 suggests that chemotaxis in response to CXCL12 may be independent of the ERK cascade. The CXCR4 (CXC chemokine receptor 4) is a member of the chemokine receptor family, which belongs to the superfamily of G protein-coupled receptors (GPCRs) 2The abbreviations used are: GPCR, G protein-coupled receptor; HEK293 cells, human embryonic kidney 293 cells; RIPA, radioimmunoprecipitation assay; siRNA, short interference RNA; USP, ubiquitin-specific protease; EGFP, enhanced green fluorescence protein; Ub, ubiquitin; ERK, extracellular signal-regulated kinase; GST, glutathione S-transferase; PBS, phosphate-buffered saline; WT, wild type; HA, hemagglutinin. (1Haribabu B. Richardson R.M. Fisher I. Sozzani S. Peiper S.C. Horuk R. Ali H. Snyderman R. J. Biol. Chem. 1997; 272: 28726-28731Abstract Full Text Full Text PDF PubMed Scopus (245) Google Scholar). Its ligand, CXCL12, also known as SDF-1α, also binds to RDC1, another chemokine receptor that is being proposed to be renamed as CXCR7 (2Balabanian K. Lagane B. Infantino S. Chow K.Y. Harriague J. Moepps B. Arenzana-Seisdedos F. Thelen M. Bachelerie F. J. Biol. Chem. 2005; 280: 35760-35766Abstract Full Text Full Text PDF PubMed Scopus (847) Google Scholar). CXCR4 mediates CXCL12-induced migration of peripheral blood lymphocytes (3Nagasawa T. Hirota S. Tachibana K. Takakura N. Nishikawa S. Kitamura Y. Yoshida N. Kikutani H. Kishimoto T. Nature. 1996; 382: 635-638Crossref PubMed Scopus (2020) Google Scholar), CD34+ progenitor cells (4Aiuti A. Webb I.J. Bleul C. Springer T. Gutierrez-Ramos J.C. J. Exp. Med. 1997; 185: 111-120Crossref PubMed Scopus (1206) Google Scholar), and pre- and pro-B cell lines (5D'Apuzzo M. Rolink A. Loetscher M. Hoxie J.A. Clark-Lewis I. Melchers F. Baggiolini M. Moser B. Eur. J. Immunol. 1997; 27: 1788-1793Crossref PubMed Scopus (287) Google Scholar). CXCR4 also plays an important role in the development of the immune system, because mouse embryos lacking either expression of the CXCR4 receptor or of its CXCL12 ligand are embryonic lethal and also manifest abnormalities in B cell lymphopoiesis and bone marrow myelopoiesis (3Nagasawa T. Hirota S. Tachibana K. Takakura N. Nishikawa S. Kitamura Y. Yoshida N. Kikutani H. Kishimoto T. Nature. 1996; 382: 635-638Crossref PubMed Scopus (2020) Google Scholar, 6Ma Q. Jones D. Borghesani P.R. Segal R.A. Nagasawa T. Kishimoto T. Bronson R.T. Springer T.A. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 9448-9453Crossref PubMed Scopus (1434) Google Scholar, 7Zou Y.R. Kottmann A.H. Kuroda M. Taniuchi I. Littman D.R. Nature. 1998; 393: 595-599Crossref PubMed Scopus (2134) Google Scholar). The altered cerebellar neuron migration in mice null for the CXCR4 receptor also suggests a role for this receptor in central nervous system development. Abnormal expression and/or function of CXCR4 have been implicated in a number of diseases, including human immunodeficiency virus infection (8Feng Y. Broder C.C. Kennedy P.E. Berger E.A. Science. 1996; 272: 872-877Crossref PubMed Scopus (3643) Google Scholar), cardiovascular disease (9Walter D.H. Haendeler J. Reinhold J. Rochwalsky U. Seeger F. Honold J. Hoffmann J. Urbich C. Lehmann R. Arenzana-Seisdesdos F. Aicher A. Heeschen C. Fichtlscherer S. Zeiher A.M. Dimmeler S. Circ. Res. 2005; 97: 1142-1151Crossref PubMed Scopus (287) Google Scholar), allergic inflammatory disease (10Abu El-Asrar A.M. Struyf S. Al-Mosallam A.A. Missotten L. Van Damme J. Geboes K. Br. J. Ophthalmol. 2001; 85: 1357-1361Crossref PubMed Scopus (44) Google Scholar), neuroinflammation (11Rauer M. Pagenstecher A. Schulte-Mönting J. Sauder C. J. Neurovirol. 2002; 8: 168-179Crossref PubMed Scopus (16) Google Scholar), neurodegenerative diseases (12Mines M. Ding Y. Fan G.H. Curr. Med. Chem. 2007; 14: 2456-2470Crossref PubMed Scopus (53) Google Scholar, 13Xia M.Q. Hyman B.T. J. Neurovirol. 1999; 5: 32-41Crossref PubMed Scopus (233) Google Scholar), and cancers (14Burger M. Glodek A. Hartmann T. Schmitt-Graff A. Silberstein L.E. Fujii N. Kipps T.J. Burger J.A. Oncogene. 2003; 22: 8093-8101Crossref PubMed Scopus (234) Google Scholar, 15Burger J.A. Kipps T.J. Blood. 2006; 107: 1761-1767Crossref PubMed Scopus (1009) Google Scholar, 16Su L. Zhang J. Xu H. Wang Y. Chu Y. Liu R. Xiong S. Clin. Cancer Res. 2005; 11: 8273-8280Crossref PubMed Scopus (137) Google Scholar, 17Saur D. Seidler B. Schneider G. Algül H. Beck R. Senekowitsch-Schmidtke R. Schwaiger M. Schmid R.M. Gastroenterology. 2005; 129: 1237-1250Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar, 18Kang H. Watkins G. Douglas-Jones A. Mansel R.E. Jiang W.G. Breast. 2005; 14: 360-367Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar, 19Cabioglu N. Sahin A. Doucet M. Yavuz E. Igci A. O Yildirim E. Aktas E. Bilgic S. Kiran B. Deniz G. Price J.E. Clin. Exp. Metast. 2005; 22: 39-46Crossref PubMed Scopus (74) Google Scholar, 20Rempel S.A. Dudas S. Ge S. Gutiérrez J.A. Clin. Cancer Res. 2000; 6: 102-111PubMed Google Scholar, 21Oh J.W. Drabik K. Kutsch O. Choi C. Tousson A. Benveniste E.N. J. Immunol. 2001; 166: 2695-2704Crossref PubMed Scopus (104) Google Scholar, 22Zhou Y. Larsen P.H. Hao C. Yong V.W. J. Biol. Chem. 2002; 277: 49481-49487Abstract Full Text Full Text PDF PubMed Scopus (328) Google Scholar, 23Woerner B.M. Warrington N.M. Kung A.L. Perry A. Rubin J.B. Cancer Res. 2005; 65: 11392-11399Crossref PubMed Scopus (90) Google Scholar, 24Hong X. Jiang F. Zhang Zhang M. K. T. M. Cancer 2006; PubMed Scopus Google Scholar). of CXCR4 (1Haribabu B. Richardson R.M. Fisher I. Sozzani S. Peiper S.C. Horuk R. Ali H. Snyderman R. J. Biol. Chem. 1997; 272: 28726-28731Abstract Full Text Full Text PDF PubMed Scopus (245) Google Scholar, M. Glodek A. Hartmann T. Schmitt-Graff A. Silberstein L.E. Fujii N. Kipps T.J. Burger J.A. Oncogene. 2003; 22: 8093-8101Crossref PubMed Scopus (234) Google Scholar, M. R. J. M. N. M. M. J. A. Blood. 2005; PubMed Scopus Google Scholar, Y. Nature. 1997; PubMed Scopus Google Scholar, Y. Q. X. T. S. Cancer Res. 2005; PubMed Google Scholar), as extracellular signal-regulated which to cell and/or of CXCR4 also induces of which are to for degradation a ubiquitination of the A. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). CXCR4 ubiquitination be by a member of the of 4) 2001; PubMed Scopus Google Scholar, A. C. F. H. 2003; 5: Full Text Full Text PDF PubMed Scopus Google Scholar). The ubiquitinated CXCR4 is to the a D. J. A. J. Biol. Chem. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar). been that deubiquitination also the and function of which the of the of in the system, implying the that is for than for that is known about the mechanisms of CXCR4 deubiquitination and by receptor that the state of USP14 was CXCL12 of cells Y. Zhang L. Wang Liu B. Zhang J. Fan G.H. Exp. Res. PubMed Scopus Google Scholar), and that ligand to enhanced association of USP14 with the The to the of this the of CXCR4 for USP14, with other USP4, and USP7, and the of the ubiquitinated state of the receptor on CXCR4 and CXCL12-induced activation of and and glutathione CXCR4 C of and of The enhanced green CXCR4 was by the of CXCR4 in and the the and of the The CXCR4 been by and and was to function as the receptor not The mutant CXCR4 that cannot be for ubiquitination was L. A. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). The USP14 was by of USP14 as and the and The was Cancer The was of The was a of of The was by the of in and the the and of the and embryonic kidney and cells in and in in fluorescence in the of HEK293 cells was or with and for CXCR4 cells with or siRNA, with CXCL12 for and in of and to which was to the to The cell was by The was by with of for to the by the was and of mouse was for an was to this and the was for The was by and the with The in of and to for of this by The to by for in a on the by the following CXCR4 was a mouse directed the in the of the USP14 was a and a directed the the of the was a directed the the of the for with the C of that with the CXCR4 C terminus, a as a the of the or with or was to the to and was for another The in and on for The of the was with for to or the with the or in and on that that to be with or C in the following HEK293 cells not CXCR4 not with but or cells as to in a and the of this used for the the the of the cell was with of the or the to for with the by and with to the CXCR4 by in for by and by as a association of CXCR4 with USP14 with other of on CXCR4 and its association with the of USP14 with CXCR4 in cells HEK293 cells with and on for or with CXCL12 for and with to cells with and with a mouse for with and with a for and with and with to on the with a was on an with a for and for and for and for the to of of CXCR4 and ligand activation of CXCR4 altered the ubiquitination of this receptor, HEK293 cells with CXCL12 for the in the and The cells in of The cell was by The was by with of for to the by the was and of mouse was for was and the was for The was by as and was with The in of and to for of this by and the to as in for The state of ubiquitination of the CXCR4 receptor was by a used to the of USP14 on CXCR4 overexpression of USP14 in HEK293 cells and RNA of endogenous USP14 in cells USP14 cells with or and and with ligand knockdown of USP14, cells with or either cells with CXCL12 for to the of ligand on the ubiquitination of the of the another of cells was for with CXCL12 by a of ligand and of the of by cell in of The cells as for of CXCR4 the of USP14 and of ubiquitination on CXCR4 and degradation, HEK293 cells CXCR4 and with for to the of with CXCL12 for to receptor ubiquitination and degradation. the cells to and in of to CXCR4 was by an The and with to the of USP14 on endogenous CXCR4 and degradation, cells, which CXCR4, with or with for to the of and with CXCL12 for the cells to and in of to CXCR4 was by an The and with to of of was The of the was in the the following of the of the in an in the as the of to for the of used to the for the migration of HEK293 cells and siRNA, or was a chemotaxis C. H. M. K. Zhang J. Fan G.H. J. Biol. Chem. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar). with human the and of the The of the was with of or CXCL12 in chemotaxis the and for in a that the the of or CXCL12 the being with a The migration was and was as number of cells the CXCL12 of cells was in that the of chemotaxis was being the receptor and not other and to the of a the of CXCL12 on mutant HA-3K/R CXCR4, cell the chemotactic of HEK293 cells with CXCR4 or HA-3K/R CXCR4 was as CXCL12-induced CXCR4-mediated ERK a for the of CXCL12-induced CXCR4-mediated cell in the activation of ERK, a of CXCR4 HEK293 cells with CXCR4 or HA-3K/R CXCR4 with CXCL12 for was by cells to and with of to and ERK was an The and with an that ERK in its and to was also to the of expression of CXCL12 to a of USP14 with of the that USP14 was a Y. M. Zhang J. N. Y. Wang S. Fan G.H. 2006; PubMed Scopus Google Scholar). that CXCL12 of HEK293 cells the receptor and to a time-dependent association of USP14 with CXCR4 USP14 association with CXCR4 was not ligand but of cells to CXCL12 to of USP14 association with the receptor the for which association receptor expression in the cells was not to USP14 to this because a for CXCL12-induced association of USP14 with was also in cells endogenous USP14 not was that USP14 interaction with CXCR4 is with other members of the family, including USP4, and USP7, which the the C of CXCR4 been to with a of ligand Y. Zhang L. Wang Liu B. Zhang J. Fan G.H. Exp. Res. PubMed Scopus Google Scholar, H. C. R. A. Zhang L. M. A.M. Zhang J. Fan G.H. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, Zhang L. A. K. Zhang J. Fan G.H. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, R. C. M. Zhang J. Fan G.H. J. Biol. Chem. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar, Y. M. Zhang J. N. Y. Wang S. Fan G.H. 2006; PubMed Scopus Google Scholar), USP14 association with CXCR4 with the C of the this a a of the of the receptor with in the with USP14 cell USP14 with whereas interaction of USP14 with We not to the cells with CXCL12 to the cell to interaction of the C with USP14 in because in in in to the cell in and the of the C was to this interaction in the of is that CXCL12 activation of the CXCR4 induces a receptor that with USP14 the receptor C cells, the C of the receptor may be in by in an receptor in in the C is and in that is not to have the cells which the is to USP14 association with the C of the The that the C of CXCR4 with USP14 of a interaction this and with the in the CXCR4 C does not in a with USP4, or not CXCL12 USP14 Co-localization with the of USP14 been to C. S. J.A. J. 2005; 95: PubMed Scopus Google and B. R.A. L. J. 2000; Scholar). We CXCL12 activation of CXCR4 to of USP14 to with the and time-dependent association of USP14 with CXCR4 in CXCL12 of HEK293 cells and to a time-dependent of on the cell and in was with a to CXCL12, which is also with the for CXCL12-induced association of CXCR4 with USP14 in and B. not observed that ligand to of CXCR4 in a of including and of CXCL12-induced CXCR4 CXCR4 ubiquitination been in cells to ubiquitination of CXCR4 only endogenous is and USP14 on this covalent with CXCL12 for of the of ubiquitination of the receptor was an in CXCL12 the of a migration in the that to as as the of CXCR4 the of ubiquitinated including C.C. 2003; PubMed Scopus Google Scholar). for the with an not that only a of the receptor was being of the CXCR4 is as for in also the for CXCR4 ubiquitination with the for CXCR4 association with USP14 as in indicates that the receptor association with USP14 to receptor ubiquitination to as be in a cycle on the receptor The in for the of CXCR4 of the receptor with CXCL12 for was by ligand cell and an observed ubiquitination of CXCR4, an and of CXCR4 ubiquitination and deubiquitination USP14 was in cells, ubiquitinated CXCR4 was the of the with are with the that not only does USP14 with CXCR4 in a in but also that USP14 this receptor as a for deubiquitination. We used a to endogenous USP14 the deubiquitination of this RNA to the expression of endogenous USP14 in HEK293 cells the CXCR4 receptor manifest a ubiquitination of CXCR4, as as a ubiquitination of the receptor following a with that the USP14 as a to the CXCR4, because its expression is is a in CXCR4 expression of endogenous USP14 the of ubiquitination of the receptor the following CXCL12 the in C and the that the USP14 contributes to a by USP14 for other been implicated as a CXCR4 for or degradation A. Sci. 1997; 22: Full Text PDF PubMed Scopus Google Scholar). of CXCR4 by USP14 be to the of receptor degradation and in an state of this HEK293 cells and USP14 with CXCL12 for or this because have that of the CXCR4 with CXCL12 of receptor degradation A. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). in with CXCL12 to an in the state of to receptor in indistinguishable of USP14, to in the state of CXCR4 was by overexpression of USP14 CXCL12-induced CXCR4 degradation. of CXCR4 by USP14 and the of USP14 on the and degradation of endogenous CXCR4, to cells, which the CXCR4 cells with or and with CXCL12 for in overexpression of in the state of CXCR4 and also blocked of CXCR4 of cells We also the of USP14 expression in cells by with in the of USP14 expression also to state of CXCR4 and of the of CXCL12 to the receptor, of to of or of CXCR4 following of expression as a in receptor the of USP14, a for this receptor, was of is an cycle of is critical for in receptor CXCR4 to for CXCL12-induced ubiquitination of CXCR4 have CXCL12-induced receptor CXCL12-mediated chemotaxis in HEK293 cells in CXCL12 to a of cells the of the with a chemotactic being and CXCL12, and because of a response C. H. M. K. Zhang J. Fan G.H. J. Biol. Chem. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar). of USP14 CXCR4-mediated chemotaxis knockdown of endogenous USP14 also CXCL12-induced chemotaxis are because are with the that is not the ubiquitinated receptor that is critical for but rather the of the receptor to an cycle as of the chemotactic for a cycle for chemotaxis is of the for a cycle for of the CXCR4 to CXCL12-induced of the of of to the of expression of USP14 is that the ubiquitination of a of be altered in with the CXCR4 as a of in USP14 CXCL12-induced chemotaxis a ubiquitination cycle that the receptor the of CXCL12 to chemotaxis of HEK293 cells either a receptor or the mutant CXCR4 that cannot be as A. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). in of the of the CXCR4 to ubiquitination also the of CXCL12 to chemotaxis of the cells this mutant the that CXCR4 mediates chemotaxis in a that a cycle on the receptor of the CXCR4 to the or of CXCL12-induced ERK of CXCR4 activation by CXCL12 is the in on in the of this by is indistinguishable in HEK293 cells an in on ERK also be by CXCL12-induced CXCR4 is that in of ERK in response to CXCL12 activation of the CXCR4, which not have only an ERK in response to CXCL12 activation of and CXCR4 a with this observed in the or the of activation of ERK CXCL12 to cells this in ERK activation following CXCL12 of by this as was with the in and ERK activation to of not The that ERK activation in cells the CXCR4 that a of CXCR4 expression is in and the of chemotaxis observed for the CXCR4 in cannot be to expression of the mutant Finally, that ERK is a of CXCL12 activation of CXCR4, this is not for chemotaxis. Although ubiquitination mechanisms and the of including cell have been the mechanisms and of deubiquitination are Our that CXCL12 activation of CXCR4, a member of the G protein-coupled receptor in ubiquitination of the receptor deubiquitination is paralleled by association of USP14 with CXCR4, an interaction that in the C of the USP14 interaction with CXCR4 is not mimicked by other of the including USP4, and CXCL12 activation of cells also to the of USP14 to by CXCR4 of been observed including the of Wang Q. M. L.E. 2005; PubMed Scopus Google and of Wang Q. M. L.E. 2005; PubMed Scopus Google Scholar, Wang Q. J. L.E. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). Our also are with the that CXCR4 a cycle that the state of on in the have been that CXCL12 of cells to receptor receptor and degradation, which to of CXCR4 that overexpression of USP14, a to an in the state of the receptor and of CXCL12-induced of receptor Although this is also observed that of USP14 expression siRNA, which receptor degradation, does observed a of the of CXCL12 to of CXCR4 following either overexpression or of USP14 that the ubiquitination cycle is the of CXCL12 of the CXCR4 to to receptor also is and that ubiquitination of the receptor is in than marking the receptor for degradation. was that the of the CXCR4 to be by the mutant of the CXCR4, as as by or USP14 expression the of this to of its in the to of chemotaxis. may in to the known role of ubiquitination in receptors for degradation, that the covalent modification of the receptor by is also important for receptor signaling. number of this role for a ubiquitination cycle on the the ubiquitinated state of the receptor a particular of the receptor, of the CXCR4, or particular receptor on the that CXCR4 in chemotaxis. chemotaxis a of a of receptors and is that the cycle on the CXCR4 also is in this gradient sensing Our that a cycle the CXCR4 receptor to be for chemotaxis the role of receptor ubiquitination a to the receptor for a particular The role of USP14 for interaction with CXCR4 is also of members of the have been to with a of receptor including the association of with the receptor C. D. M. B. E. S. A. A. S. J. M. Cancer Res. 2006; PubMed Scopus Google and with the receptor T. E. E. E. S. M. C. 2006; PubMed Scopus Google Scholar). are the to a interaction of USP14 with Our that the C of CXCR4, on its with USP14 may be to the of a in this of CXCR4 for receptor degradation A. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). is also important to that the C of the CXCR4 receptor, the members and and USP14 not is of that the ubiquitination of Our a of the CXCR4 receptor in response to CXCL12 that be with an to endogenous also that this only a of the receptor because an the used to on also not of the not a of the CXCR4 receptor in response to CXCL12 but the of following of a this A. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). We that the in of the ubiquitinated CXCR4 receptor following CXCL12 is because of in of was the observation that the of ERK activation by CXCL12-induced activation of CXCR4 was indistinguishable for the and receptor that a independent of ERK activation CXCL12 activation of the receptor to chemotaxis. that CXCL12 activation of the CXCR4 to a cycle and that USP14 with and The of this cycle not only receptor degradation but also chemotaxis. the that of the cycle have a of as as that may be a of a of other We of and of for the of and CXCR4 We L. for with the mutant CXCR4 Cancer for with the of for with the and of of for the of
No takes yet. Share an insight, caveat, or question.
Mines et al. (2008) studied this question.