PMID- 22142194
OWN - NLM
STAT- MEDLINE
DCOM- 20120409
LR  - 20231019
IS  - 1470-8728 (Electronic)
IS  - 0264-6021 (Print)
IS  - 0264-6021 (Linking)
VI  - 442
IP  - 2
DP  - 2012 Mar 1
TI  - Secreted CXCL12 (SDF-1) forms dimers under physiological conditions.
PG  - 433-42
LID - 10.1042/BJ20111341 [doi]
AB  - Chemokine CXCL12 (CXC chemokine ligand 12) signalling through CXCR (CXC chemokine 
      receptor) 4 and CXCR7 has essential functions in development and underlies 
      diseases including cancer, atherosclerosis and autoimmunity. Chemokines may form 
      homodimers that regulate receptor binding and signalling, but previous studies 
      with synthetic CXCL12 have produced conflicting evidence for homodimerization. We 
      used bioluminescence imaging with GL (Gaussia luciferase) fusions to investigate 
      dimerization of CXCL12 secreted from mammalian cells. Using column chromatography 
      and GL complementation, we established that CXCL12 was secreted from mammalian 
      cells as both monomers and dimers. Secreted CXCL12 also formed homodimers in the 
      extracellular space. Monomeric CXCL12 preferentially activated CXCR4 signalling 
      through Galphai and Akt, whereas dimeric CXCL12 more effectively promoted recruitment 
      of beta-arrestin 2 to CXCR4 and chemotaxis of CXCR4-expressing breast cancer cells. 
      We also showed that CXCR7 preferentially sequestered monomeric CXCL12 from the 
      extracellular space and had minimal effects on dimeric CXCL12 in cell-based 
      assays and an orthotopic tumour xenograft model of human breast cancer. These 
      studies establish that CXCL12 secreted from mammalian cells forms homodimers 
      under physiological conditions. Since monomeric and dimeric CXCL12 have distinct 
      effects on cell signalling and function, our results have important implications 
      for ongoing efforts to target CXCL12 pathways for therapy.
FAU - Ray, Paramita
AU  - Ray P
AD  - Center for Molecular Imaging, Department of Radiology, University of Michigan, 
      Ann Arbor, MI 48109, U.S.A.
FAU - Lewin, Sarah A
AU  - Lewin SA
FAU - Mihalko, Laura Anne
AU  - Mihalko LA
FAU - Lesher-Perez, Sasha-Cai
AU  - Lesher-Perez SC
FAU - Takayama, Shuichi
AU  - Takayama S
FAU - Luker, Kathryn E
AU  - Luker KE
FAU - Luker, Gary D
AU  - Luker GD
LA  - eng
GR  - T32 GM008353/GM/NIGMS NIH HHS/United States
GR  - R01CA136553/CA/NCI NIH HHS/United States
GR  - R01CA136829/CA/NCI NIH HHS/United States
GR  - R01 CA136829/CA/NCI NIH HHS/United States
GR  - T32 GM145304/GM/NIGMS NIH HHS/United States
GR  - R01 CA136553/CA/NCI NIH HHS/United States
GR  - P50CA093990/CA/NCI NIH HHS/United States
GR  - P50 CA093990/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PL  - England
TA  - Biochem J
JT  - The Biochemical journal
JID - 2984726R
RN  - 0 (ACKR3 protein, human)
RN  - 0 (CXCL12 protein, human)
RN  - 0 (CXCR4 protein, human)
RN  - 0 (Chemokine CXCL12)
RN  - 0 (Receptors, CXCR)
RN  - 0 (Receptors, CXCR4)
RN  - 0 (Recombinant Fusion Proteins)
RN  - EC 1.13.12.7 (Luciferases, Firefly)
SB  - IM
MH  - Animals
MH  - Breast Neoplasms/metabolism
MH  - Cell Line, Tumor
MH  - Chemokine CXCL12/*chemistry/genetics/*physiology
MH  - Dimerization
MH  - Extracellular Space/metabolism
MH  - Female
MH  - HEK293 Cells
MH  - Humans
MH  - Luciferases, Firefly/genetics/metabolism
MH  - Mice
MH  - Mice, Inbred NOD
MH  - Mice, SCID
MH  - Neoplasm Transplantation
MH  - Protein Structure, Quaternary
MH  - Receptors, CXCR/metabolism
MH  - Receptors, CXCR4/metabolism
MH  - Recombinant Fusion Proteins/chemistry/genetics/metabolism
MH  - Signal Transduction
MH  - Transplantation, Heterologous
PMC - PMC4419379
MID - NIHMS684613
EDAT- 2011/12/07 06:00
MHDA- 2012/04/10 06:00
PMCR- 2015/05/05
CRDT- 2011/12/07 06:00
PHST- 2011/12/07 06:00 [entrez]
PHST- 2011/12/07 06:00 [pubmed]
PHST- 2012/04/10 06:00 [medline]
PHST- 2015/05/05 00:00 [pmc-release]
AID - BJ20111341 [pii]
AID - 10.1042/BJ20111341 [doi]
PST - ppublish
SO  - Biochem J. 2012 Mar 1;442(2):433-42. doi: 10.1042/BJ20111341.