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Blood, 15 July 2004, Vol. 104, No. 2, pp. 302-303.
CB2, a paradigm for a novel class of "onco-GPCRs"?SANOFI-SYNTHELABO
Further supporting the transforming potential of CB2, the peripheral cannabinoid receptor, Alberich Jordà and colleagues characterized the ligand-dependent signaling of the CB2-mediated neutrophilic differentiation blockade and cell-migration stimulation.
In this issue of Blood, Alberich Jordà and colleagues (page 526) present original data on the putative mechanism of CB2-mediated transformation. They showed that 2 different CB2 ligands elicited distinct effects on cell migration and differentiation of CB2-expressing myeloid precursor cells. Using murine normal bone marrow precursor cells and 32D/granulocyte colony-stimulating factor receptor (G-CSF-R) cells, where high CB2 expression was achieved by transfection of a CB2-enhanced green fluorescent protein (EGFP) fusion construct, they showed that 2-arachidonoylglycerol (2-AG) dose dependently stimulated cell migration and did not affect neutrophilic differentiation. Conversely, CP55940, which did not affect cell migration, blocked neutrophilic differentiation. Both effects were abolished by the specific CB2 antagonist, SR144528, and by pertussis toxin (PTX), indicating a CB2-mediated and a G This work of Alberich Jordà and colleagues complements their previous reports on the transforming potential of CB2, and their findings raise the intriguing question of the mechanisms behind the distinct effects elicited by the 2 ligands. GPCR signaling is more complex than initially thought, and it is now well established that a wide variety of GPCRs can form homo-oligomeric complexes and can hetero-oligomerize with other GPCRs or unrelated membrane proteins.4 This property enables functional cross-talk and generates alternative signaling properties upon ligand binding. CB1, the central cannabinoid receptor, was recently demonstrated to potentiate the orexigenic receptor, OX1R, through functional cross-talk when the 2 receptors are coexpressed.5 To date, it is not known whether CB2 shares this ability to form multimeric complexes. Further studies are warranted to clarify this important issue. In this context, a better understanding of CB2 signaling may open new avenues for therapeutic interventions to treat leukemia. References
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| Copyright © 2004 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||||
i protein-dependent mechanism. In the second part of their study, the authors investigated the signaling pathway downstream receptor activation and showed that CB2-mediated migration involved cyclic adenosine monophosphate (cAMP) and mitogen-induced extracellular kinase/extracellular signal-related kinase (MEK/ERK), whereas differentiation block involved only MEK/ERK. Finally, using CB2-DRY mutants, they also showed that the CB2-mediated block of differentiation did not require the DRY-dependent G-protein recruitment, which suggests the involvement of alternative mechanisms of activation. 