Secreted CXCL12 (SDF-1) forms dimers under physiological conditions

Area of Science:

• Molecular Biology
• Cellular Signaling
• Biochemistry

Background:

• Chemokine CXCL12 (CXC chemokine ligand 12) signaling via CXCR4 and CXCR7 is crucial in development and disease.
• Previous studies on CXCL12 homodimerization have yielded conflicting results.
• Understanding CXCL12's functional states is vital for therapeutic targeting.

Purpose of the Study:

• To investigate the dimerization status of CXCL12 secreted from mammalian cells.
• To determine the distinct roles of monomeric and dimeric CXCL12 in receptor activation and cell function.
• To elucidate the differential interactions of CXCL12 monomers and dimers with CXCR4 and CXCR7.

Main Methods:

• Bioluminescence imaging using Gaussia luciferase (GL) fusions.
• GL complementation assays.
• Column chromatography.
• Cell-based assays and orthotopic tumor xenograft models.

Main Results:

• CXCL12 is secreted from mammalian cells as both monomers and dimers and forms homodimers extracellularly.
• Monomeric CXCL12 preferentially activates CXCR4 signaling via Gαi/Akt.
• Dimeric CXCL12 enhances β-arrestin 2 recruitment to CXCR4 and promotes chemotaxis of breast cancer cells.
• CXCR7 preferentially sequesters monomeric CXCL12 with minimal effect on dimeric CXCL12.

Conclusions:

• Secreted CXCL12 forms homodimers under physiological conditions.
• Monomeric and dimeric CXCL12 exhibit distinct functional activities.
• These findings have significant implications for targeting CXCL12 pathways in diseases like cancer.