Calcium-RasGRP2-Rap1 signaling mediates CD38-induced migration of chronic lymphocytic leukemia cells

Mele, Sylvia, Devereux, Stephen, Pepper, Andrea G, Infante, Elvira and Ridley, Anne J (2018) Calcium-RasGRP2-Rap1 signaling mediates CD38-induced migration of chronic lymphocytic leukemia cells. Blood Advances, 2 (13). pp. 1551-1561. ISSN 2473-9529

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Abstract

CD38 is a transmembrane exoenzyme that is associated with poor prognosis in chronic lymphocytic leukemia (CLL). High CD38 levels in CLL cells are linked to increased cell migration, but the molecular basis is unknown. CD38 produces nicotinic acid adenine dinucleotide phosphate and adenosine 5′-diphosphate-ribose, both of which can act to increase intracellular Ca2+ levels. Here we show that CD38 expression increases basal intracellular Ca2+ levels and stimulates CLL cell migration both with and without chemokine stimulation. We find that CD38 acts via intracellular Ca2+ to increase the activity of the Ras family GTPase Rap1, which is in turn regulated by the Ca2+-sensitive Rap1 guanine-nucleotide exchange factor RasGRP2. Both Rap1 and RasGRP2 are required for CLL cell migration, and RasGRP2 is polarized in primary CLL cells with high CD38 levels. These results indicate that CD38 promotes RasGRP2/Rap1-mediated CLL cell adhesion and migration by increasing intracellular Ca2+ levels.

Item Type: Article
Keywords: CLL, CD38,Calcium-RasGRP2-Rap1,leukemia, Cancer, lymphoid
Schools and Departments: Brighton and Sussex Medical School > Clinical and Experimental Medicine
Research Centres and Groups: Haematology Research Group
Subjects: R Medicine
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Depositing User: Gemma Hamilton
Date Deposited: 16 Aug 2018 13:06
Last Modified: 14 Mar 2019 16:10
URI: http://sro.sussex.ac.uk/id/eprint/77648

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