Differential effects of G protein coupled receptors on hematopoietic progenitor cell growth depend on their signaling capacities.
We have shown that CD34(+) hematopoietic progenitor and stem cells (HPCs) consistently express several G protein-coupled receptors (GPCRs): the chemokine receptor CXCR4, the cysteinyl-leukotriene receptor cysLT1, and receptors for sphingosine 1-phosphate (S1P), particularly S1P1. These GPCRs differentially mediate chemotactic, adhesive, and proliferative responses in HPCs. To elucidate the diversity of the responses observed, we compared their signaling capacities in CD34(+) cells. In primary CD34(+) progenitors, the strongest effects on calcium signaling (intracellular calcium fluxes) were mediated by cysLT1. Analyses in CD34(+) cell lines revealed that calcium signaling induced by cysLT1 was only partially inhibited by pertussis toxin (PTX), while responses induced by CXCR4 and S1P receptors were completely blocked. These findings indicate that cysLT1 signals via Gi and Gq proteins, while CXCR4 and also S1P receptors (e.g., S1P1) only induce Gi protein-mediated effects. By analysis of downstream signaling, we could provide further evidence that combined activation of PTX-insensitive (Gq-mediated) and PTX-sensitive (Gi-mediated) pathways by cysLT1 may explain the strong and broad effects of cysteinyl-leukotrienes in early hematopoietic cells, while signaling of CXCR4 and S1P1 solely depends on Gi proteins, resulting in effects mainly restricted to migration and adhesion.
Xue
Xingkui
X
Department of Medicine II, University of Tübingen, Otfried-Müller-Str. 10, 72076 Tübingen, Germany.
Cai
Zhen
Z
Seitz
Gabriele
G
Kanz
Lothar
L
Weisel
Katja C
KC
Möhle
Robert
R
D018952:Antigens, CD34 / Q000096:biosynthesis; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D002460:Cell Line; D049109:Cell Proliferation; D051418:Focal Adhesion Kinase 2 / Q000378:metabolism; D005786:Gene Expression Regulation; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D006801:Humans; D008246:Lysophospholipids / Q000378:metabolism; D008954:Models, Biological; D037342:Pertussis Toxin / Q000378:metabolism / Q000494:pharmacology; D010766:Phosphorylation; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism; D013997:Time Factors
D018952:Antigens, CD34; D008246:Lysophospholipids; C060506:sphingosine 1-phosphate; D037342:Pertussis Toxin; D051418:Focal Adhesion Kinase 2; D013110:Sphingosine; D002118:Calcium