An essential role of the cytoplasmic tail of CXCR4 in G-protein signaling and organogenesis

PLoS One. 2010 Nov 19;5(11):e15397. doi: 10.1371/journal.pone.0015397.


CXCR4 regulates cell proliferation, enhances cell survival and induces chemotaxis, yet molecular mechanisms underlying its signaling remain elusive. Like all other G-protein coupled receptors (GPCRs), CXCR4 delivers signals through G-protein-dependent and -independent pathways, the latter involving its serine-rich cytoplasmic tail. To evaluate the signaling and biological contribution of this G-protein-independent pathway, we generated mutant mice that express cytoplasmic tail-truncated CXCR4 (ΔT) by a gene knock-in approach. We found that ΔT mice exhibited multiple developmental defects, with not only G-protein-independent but also G-protein-dependent signaling events completely abolished, despite ΔT's ability to still associate with G-proteins. These results reveal an essential positive regulatory role of the cytoplasmic tail in CXCR4 signaling and suggest the tail is crucial for mediating G-protein activation and initiating crosstalk between G-protein-dependent and G-protein-independent pathways for correct GPCR signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Adhesion / genetics
  • Chemokine CXCL12 / metabolism
  • Chemokine CXCL12 / pharmacology
  • Chemotaxis / drug effects
  • Female
  • Flow Cytometry
  • GTP-Binding Proteins / genetics
  • GTP-Binding Proteins / metabolism*
  • Gastric Mucosa / metabolism
  • HEK293 Cells
  • Humans
  • Immunoblotting
  • Immunoprecipitation
  • Male
  • Mice
  • Mice, Knockout
  • Organogenesis*
  • Precursor Cells, B-Lymphoid / metabolism
  • Precursor Cells, B-Lymphoid / physiology
  • Protein Binding
  • Receptors, CXCR4 / genetics
  • Receptors, CXCR4 / metabolism
  • Receptors, CXCR4 / physiology*
  • Signal Transduction*
  • Stomach / embryology
  • Time Factors


  • CXCR4 protein, mouse
  • Chemokine CXCL12
  • Cxcl12 protein, mouse
  • Receptors, CXCR4
  • GTP-Binding Proteins