RGS16 is a negative regulator of SDF-1-CXCR4 signaling in megakaryocytes.
Regulators of G-protein signaling (RGS) constitute a family of proteins involved in the negative regulation of signaling through heterotrimeric G protein-coupled receptors (GPCRs). Several RGS proteins have been implicated in the down-regulation of chemokine signaling in hematopoietic cells. The chemokine stromal-cell-derived factor 1 (SDF-1) activates migration of hematopoietic progenitors cells but fails to activate mature megakaryocytes despite high levels of CXC chemokine receptor 4 (CXCR4) receptor expression in these cells. This prompted us to analyze RGS expression and function during megakaryocyte differentiation. We found that RGS16 and RGS18 mRNA expression was up-regulated during this process. Overexpressing RGS16 mRNA in the megakaryocytic MO7e cell line inhibited SDF-1-induced migration, mitogen-activated protein kinase (MAPK) and protein kinase B (AKT) activation, whereas RGS18 overexpression had no effect on CXCR4 signaling. Knocking down RGS16 mRNA via lentiviral-mediated RNA interference increased CXCR4 signaling in MO7e cells and in primary megakaryocytes. Thus, our data reveal that RGS16 is a negative regulator of CXCR4 signaling in megakaryocytes. We postulate that RGS16 regulation is a mechanism that controls megakaryocyte maturation by regulating signals from the microenvironment.
Institut National de la Santé et de la Recherche Médicale (INSERM) U 362, Institut Gustave Roussy, Villejuif, France.
Magali
M
Berthebaud
Christel
C
Rivière
Peggy
P
Jarrier
Adlen
A
Foudi
Yanyan
Y
Zhang
Daniel
D
Compagno
Anne
A
Galy
William
W
Vainchenker
Fawzia
F
Louache
D001792:Blood Platelets / Q000166:cytology / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000235:genetics / Q000378:metabolism*; D002633:Chemotaxis; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D008533:Megakaryocytes / Q000166:cytology / Q000378:metabolism*; D009690:Nucleic Acid Conformation; D011506:Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020710:RGS Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000378:metabolism*; D015398:Signal Transduction; D015854:Up-Regulation
C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D011506:Proteins; D020710:RGS Proteins; C107413:RGS16 protein; D019718:Receptors, CXCR4; D048049:Extracellular Signal-Regulated MAP Kinases