PMID- 28455789
OWN - NLM
STAT- MEDLINE
DCOM- 20180806
LR  - 20210604
IS  - 1573-4919 (Electronic)
IS  - 0300-8177 (Print)
IS  - 0300-8177 (Linking)
VI  - 434
IP  - 1-2
DP  - 2017 Oct
TI  - Functional and structural consequences of chemokine (C-X-C motif) receptor 4 
      activation with cognate and non-cognate agonists.
PG  - 143-151
LID - 10.1007/s11010-017-3044-7 [doi]
AB  - Chemokine (C-X-C motif) receptor 4 (CXCR4) regulates cell trafficking and plays 
      important roles in the immune system. Ubiquitin has recently been identified as 
      an endogenous non-cognate agonist of CXCR4, which activates CXCR4 via interaction 
      sites that are distinct from those of the cognate agonist C-X-C motif chemokine 
      ligand 12 (CXCL12). As compared with CXCL12, chemotactic activities of ubiquitin 
      in primary human cells are poorly characterized. Furthermore, evidence for 
      functional selectivity of CXCR4 agonists is lacking, and structural consequences 
      of ubiquitin binding to CXCR4 are unknown. Here, we show that ubiquitin and 
      CXCL12 have comparable chemotactic activities in normal human peripheral blood 
      mononuclear cells, monocytes, vascular smooth muscle, and endothelial cells. 
      Chemotactic activities of the CXCR4 ligands could be inhibited with the selective 
      CXCR4 antagonist AMD3100 and with a peptide analogue of the second transmembrane 
      domain of CXCR4. In human monocytes, ubiquitin- and CXCL12-induced chemotaxis 
      could be inhibited with pertussis toxin and with inhibitors of phospholipase C, 
      phosphatidylinositol 3 kinase, and extracellular signal-regulated kinase 1/2. 
      Both agonists induced inositol trisphosphate production in vascular smooth muscle 
      cells, which could be inhibited with AMD3100. In beta-arrestin recruitment assays, 
      ubiquitin did not sufficiently recruit beta-arrestin2 to CXCR4 (EC(50) > 10 muM), 
      whereas the EC(50) for CXCL12 was 4.6 nM (95% confidence interval 3.1-6.1 nM). 
      Both agonists induced similar chemical shift changes in the 
      (13)C-(1)H-heteronuclear single quantum correlation (HSQC) spectrum of CXCR4 in 
      membranes, whereas CXCL11 did not significantly alter the (13)C-(1)H-HSQC 
      spectrum of CXCR4. Our findings point towards ubiquitin as a biased agonist of 
      CXCR4.
FAU - Eby, Jonathan M
AU  - Eby JM
AD  - Department of Surgery, Burn and Shock Trauma Research Institute, Loyola 
      University Chicago Stritch School of Medicine, 2160 S. First Avenue, Maywood, IL, 
      60153, USA.
FAU - Abdelkarim, Hazem
AU  - Abdelkarim H
AD  - Department of Biochemistry and Molecular Genetics, University of Illinois at 
      Chicago, 900 S Ashland, Chicago, IL, 60607, USA.
FAU - Albee, Lauren J
AU  - Albee LJ
AD  - Department of Surgery, Burn and Shock Trauma Research Institute, Loyola 
      University Chicago Stritch School of Medicine, 2160 S. First Avenue, Maywood, IL, 
      60153, USA.
FAU - Tripathi, Abhishek
AU  - Tripathi A
AD  - Department of Surgery, Burn and Shock Trauma Research Institute, Loyola 
      University Chicago Stritch School of Medicine, 2160 S. First Avenue, Maywood, IL, 
      60153, USA.
FAU - Gao, Xianlong
AU  - Gao X
AD  - Department of Surgery, Burn and Shock Trauma Research Institute, Loyola 
      University Chicago Stritch School of Medicine, 2160 S. First Avenue, Maywood, IL, 
      60153, USA.
FAU - Volkman, Brian F
AU  - Volkman BF
AD  - Department of Biochemistry, Medical College of Wisconsin, 8701 Watertown Plank 
      Road, Milwaukee, WI, 53226, USA.
FAU - Gaponenko, Vadim
AU  - Gaponenko V
AD  - Department of Biochemistry and Molecular Genetics, University of Illinois at 
      Chicago, 900 S Ashland, Chicago, IL, 60607, USA.
FAU - Majetschak, Matthias
AU  - Majetschak M
AD  - Department of Surgery, Burn and Shock Trauma Research Institute, Loyola 
      University Chicago Stritch School of Medicine, 2160 S. First Avenue, Maywood, IL, 
      60153, USA. mmajetschak@luc.edu.
AD  - Department of Molecular Pharmacology and Therapeutics, Loyola University Chicago 
      Stritch School of Medicine, 2160 S. First Avenue, Maywood, IL, 60153, USA. 
      mmajetschak@luc.edu.
LA  - eng
GR  - R37 AI058072/AI/NIAID NIH HHS/United States
GR  - R21HL118588/the National Heart, Lung, and Blood Institute/
GR  - R01 GM107495/GM/NIGMS NIH HHS/United States
GR  - W81XWH-15-1-0262/Office of the Assistant Secretary of Defense for Health Affairs 
      through the Peer Reviewed Medical Research Program/
GR  - R21 HL118588/HL/NHLBI NIH HHS/United States
GR  - R01GM107495/GM/NIGMS NIH HHS/United States
GR  - R01 AI058072/AI/NIAID NIH HHS/United States
GR  - R01 CA188427/CA/NCI NIH HHS/United States
GR  - R01CA188427/CA/NCI NIH HHS/United States
PT  - Journal Article
DEP - 20170428
PL  - Netherlands
TA  - Mol Cell Biochem
JT  - Molecular and cellular biochemistry
JID - 0364456
RN  - 0 (CXCL12 protein, human)
RN  - 0 (CXCR4 protein, human)
RN  - 0 (Chemokine CXCL12)
RN  - 0 (Receptors, CXCR4)
RN  - 0 (Ubiquitin)
SB  - IM
MH  - Chemokine CXCL12/metabolism
MH  - Chemotaxis
MH  - Enzyme-Linked Immunosorbent Assay
MH  - Humans
MH  - Nuclear Magnetic Resonance, Biomolecular
MH  - Protein Conformation
MH  - Receptors, CXCR4/agonists/chemistry/*metabolism
MH  - Signal Transduction
MH  - Ubiquitin/metabolism
PMC - PMC5660673
MID - NIHMS871568
OTO - NOTNLM
OT  - Biased agonist
OT  - CXCL12
OT  - Chemotaxis
OT  - Nuclear magnetic resonance spectroscopy
OT  - Stromal cell-derived factor-1alpha
OT  - Ubiquitin
COIS- Conflict of Interest The authors declare no conflict of interest.
EDAT- 2017/04/30 06:00
MHDA- 2018/08/07 06:00
PMCR- 2018/10/01
CRDT- 2017/04/30 06:00
PHST- 2017/02/13 00:00 [received]
PHST- 2017/04/22 00:00 [accepted]
PHST- 2017/04/30 06:00 [pubmed]
PHST- 2018/08/07 06:00 [medline]
PHST- 2017/04/30 06:00 [entrez]
PHST- 2018/10/01 00:00 [pmc-release]
AID - 10.1007/s11010-017-3044-7 [pii]
AID - 10.1007/s11010-017-3044-7 [doi]
PST - ppublish
SO  - Mol Cell Biochem. 2017 Oct;434(1-2):143-151. doi: 10.1007/s11010-017-3044-7. Epub 
      2017 Apr 28.