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Blood, 1 November 2005, Vol. 106, No. 9, pp. 2928-2929.
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CHEMOKINES, CYTOKINES, AND INTERLEUKINS
Comment on Berthebaud et al, page 2962
RGS16 "tightens the reins" on CXCR4
Mariusz Z. Ratajczak
JAMES GRAHAM BROWN CANCER CENTER
While expression of CXCR4, the receptor for the  -chemokine stromal-derived factor 1 (SDF-1), is relatively high on mature megakaryocytes, these cells lose their responsiveness to stimulation by SDF-1 compared with young megakaryoblasts. RGS16, a member of the regulators of G-protein signaling (RGS) family, is found to be responsible for this effect.
The CXC chemokine receptor 4 (CXCR4)–stromal-derived factor 1 (SDF-1) axis plays an important role in the maturation of megakaryocytes (MKs) by promoting their developmental translocation from the osteoblastic niche to the endothelial niche and is thus involved in MK maturation and proplatelet formation.1 CXCR4 is highly expressed on MKs; however, the chemotactic responsiveness of these cells to an SDF-1 gradient, which is robust with early megakaryoblasts, decreases with maturation of MKs.2 A similar phenomenon was found for maturing B-lymphocytic cells in bone marrow (BM).3 Involvement of regulators of G-protein signaling (RGS) proteins was suspected in these phenomena and a hunt to identify these proteins began. The RGS proteins function as guanosine triphosphate (GTP)–activating proteins (GAPs) for G subunits, accelerating the inactivation of G-GTP. RGS may also block signaling by acting as effector antagonists. Expression of RGS proteins seems to be hematopoietic-lineage specific and cell-maturation dependent.
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Different levels of regulation of CXCR4 function on hematopoietic cells. First, expression of CXCR4 is regulated at the transcriptional level by several factors (eg, hypoxia). Second, CXCR4 as well as its ligand SDF-1 are subject to proteolytic degradation by several proteases that are expressed in the hematopoietic microenvironment and serum. Third, CXCR4 after interaction with SDF-1 is internalized from the surface and is recirculated from the endosomal compartment at different rates. Fourth, functionality of the CXCR4 receptor depends on its incorporation into membrane lipid rafts, and several signals from other membrane receptors or integrins may increase the incorporation of CXCR4 into membrane lipid rafts, increasing its signaling.4 Finally, as demonstrated by Berthebaud et al, CXCR4 is the subject of negative regulation by RGS16. It is possible that this mechanism plays a role in heterologous desensitization or negative cross-talk of CXCR4 after stimulation of MKs by other chemokines (eg, macrophage inflammatory protein 1 [MIP-1] or interleukin-8 [IL-8]).
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An RGS protein that modulates the chemotactic responsiveness of MKs to SDF-1 has been identified in an elegant study by Berthebaud and colleagues. Using several complementary strategies, they identified RGS16 as responsible for this effect. They found RGS16 to be up-regulated during MK maturation and differentiation. Overexpressing RGS16 mRNA in the megakaryocytic MO7e cell line inhibited SDF-1–induced migration. On the other hand, knocking-down RGS16 mRNA via lentiviral-mediated RNA interference increased CXCR4 signaling both in MO7e cells and primary MKs. Based on this, Berthebaud et al postulate that RGS16 regulation is a mechanism that controls MK chemotaxis to an SDF-1 gradient and MK developmental migration within the BM microenvironment. RGS16 inhibits SDF-1–mediated phosphorylation of mitogen-activated protein kinase p42/44 (MAPKp42/44) and protein kinase B (AKT) in MO7e cells. Surprisingly, however, RGS16 does not seem to influence colonyforming unit (CFU)–MK growth, MK adhesion to either fibronectin or collagen I, and proplatelet formation.
Thus, a multilevel model of regulation of the CXCR4 –SDF-1 axis on MKs and other hematopoietic cells emerges from this and other studies, and, as is shown in the figure, RGS16 emerges as a pivotal negative regulator of CXCR4 signaling in MKs.
Such regulation of CXCR4 signaling in MKs by RGS16 raises further questions. First, it would be important to identify factors/cytokines that directly modulate the expression of RGS16 in MKs. Second, since CXCR4 is also highly expressed on platelets, one can ask whether RGS16 is also responsible for inhibition of CXCR4 signaling on these cells.2 Third, since the responsiveness of MKs (M.Z.R., unpublished observations, 2003), like B lymphocytes,3 is inhibited by the -chemokine MIP-1 that binds to CC chemokine receptor 5 (CCR5), it is possible that the CCR5–MIP-1 axis mediates this effect by up-regulating RGS16 in MKs and another B-cell lineage–specific RGS protein in B lymphocytes.3 Fourth, are RGS proteins involved in trafficking of hematopoietic stem/progenitor cells (HSPCs)? Would, for example, overexpression of HSPC-specific RGS proteins increase their mobilization, or, in contrast, would a decrease in their expression increase homing of HSPCs into BM?5 Is it possible that certain chemokines that induce mobilization of HSPCs (eg, MIP-1, IL-8, or growth-related oncogene [GRO-]) operate by heterologous desensitization of CXCR4, and are RGS proteins involved in this process?6,7
Since RGS16 modulates the responsiveness of MKs to SDF-1, this may affect their migration within the hematopoietic environment and, most importantly, their translocation between the osteoblastic and endothelial niches.1 However, the effect of RGS16 on SDF-1–mediated polyploidization was not investigated in this study. The current data can be verified and new questions answered when RGS16 knock-out mice become available. Further studies will also address whether RGS16 negatively regulates the potential responsiveness of platelets to SDF-1.2
There is no doubt that identification of a specific RGS protein that "tightens the reins" on CXCR4 on MKs is an important step forward in understanding the regulation of signaling by this intriguing receptor. 
References
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- Majka M, Janowska-Wieczorek A, Ratajczak J, et al. Stromal-derived factor 1 and thrombopoietin regulate distinct aspects of human megakaryopoiesis. Blood. 2000;96: 4142-4151.[Abstract/Free Full Text]
- Honczarenko M, Le Y, Glodek AM, et al. CCR5-binding chemokines modulate CXCL12 (SDF-1)-induced responses of progenitor B cells in human bone marrow through heterologous desensitization of the CXCR4 chemokine receptor. Blood. 2002;100: 2321-2329.[Abstract/Free Full Text]
- Wysoczynski M, Reca R, Ratajczak J, et al. Incorporation of CXCR4 into membrane lipid rafts primes homing-related responses of hematopoietic stem/progenitor cells to an SDF-1 gradient. Blood. 2005;105: 40-48.[Abstract/Free Full Text]
- Lapidot T, Dar A, Kollet O. How do stem cells find their way home? Blood. Prepublished on May 12, 2005, as DOI 10.1182/blood-2005-04-1417.[Abstract/Free Full Text]
- Papayannopoulou T. Current mechanistic scenarios in hematopoietic stem/progenitor cell mobilization. Blood. 2004;103: 1580-1585.[Abstract/Free Full Text]
- King AG, Horowitz D, Dillon SB, et al. Rapid mobilization of murine hematopoietic stem cells with enhanced engraftment properties and evaluation of hematopoietic progenitor cell mobilization in rhesus monkeys by a single injection of SB-251353, a specific truncated form of the human CXC chemokine GRObeta. Blood. 2001;97: 1534-1542.[Abstract/Free Full Text]
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RGS16 is a negative regulator of SDF-1–CXCR4 signaling in megakaryocytes
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