An essential role of the cytoplasmic tail of CXCR4 in G-protein signaling and organogenesis.
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.
Center for Autoimmune and Musculoskeletal Diseases, Feinstein Institute for Medical Research, Manhasset, New York, USA.
Darran G
DG
Cronshaw
Yuchun
Y
Nie
Janelle
J
Waite
Yong-Rui
YR
Zou
D000818:Animals; D002448:Cell Adhesion / Q000235:genetics; D054377:Chemokine CXCL12 / Q000378:metabolism / Q000494:pharmacology; D002633:Chemotaxis / Q000187:drug effects; D005260:Female; D005434:Flow Cytometry; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005753:Gastric Mucosa / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D038081:Organogenesis; D054448:Precursor Cells, B-Lymphoid / Q000378:metabolism / Q000502:physiology; D011485:Protein Binding; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D013270:Stomach / Q000196:embryology; D013997:Time Factors
C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D019718:Receptors, CXCR4; D019204:GTP-Binding Proteins