Differential effects of G protein coupled receptors on hematopoietic progenitor cell growth depend on their signaling capacities

TY - JOUR

T1 - Differential effects of G protein coupled receptors on hematopoietic progenitor cell growth depend on their signaling capacities

AU - Xue, Xingkui

AU - Cai, Zhen

AU - Seitz, Gabriele

AU - Kanz, Lothar

AU - Weisel, Katja C

AU - Möhle, Robert

PY - 2007/6

Y1 - 2007/6

N2 - 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.

AB - 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.

KW - Antigens, CD34

KW - Calcium

KW - Calcium Signaling

KW - Cell Line

KW - Cell Proliferation

KW - Focal Adhesion Kinase 2

KW - Gene Expression Regulation

KW - Hematopoietic Stem Cells

KW - Humans

KW - Lysophospholipids

KW - Models, Biological

KW - Pertussis Toxin

KW - Phosphorylation

KW - Signal Transduction

KW - Sphingosine

KW - Time Factors

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1196/annals.1392.014

DO - 10.1196/annals.1392.014

M3 - SCORING: Journal article

C2 - 17360805

VL - 1106

SP - 180

EP - 189

JO - ANN NY ACAD SCI

JF - ANN NY ACAD SCI

SN - 0077-8923

ER -