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

TY - JOUR

T1 - Calcium-RasGRP2-Rap1 signaling mediates CD38-induced migration of chronic lymphocytic leukemia cells

AU - Mele, Silvia

AU - Devereux, Stephen

AU - Pepper, Andrea G.

AU - Infante, Elvira

AU - Ridley, Anne J.

PY - 2018/7/10

Y1 - 2018/7/10

N2 - 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 59-diphosphate-ribose, both of which can act to increase intracellular Ca21 levels. Here we show that CD38 expression increases basal intracellular Ca21 levels and stimulates CLL cell migration both with and without chemokine stimulation. We find that CD38 acts via intracellular Ca21 to increase the activity of the Ras family GTPase Rap1, which is in turn regulated by the Ca21-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 Ca21 levels.

AB - 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 59-diphosphate-ribose, both of which can act to increase intracellular Ca21 levels. Here we show that CD38 expression increases basal intracellular Ca21 levels and stimulates CLL cell migration both with and without chemokine stimulation. We find that CD38 acts via intracellular Ca21 to increase the activity of the Ras family GTPase Rap1, which is in turn regulated by the Ca21-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 Ca21 levels.

UR - http://www.scopus.com/inward/record.url?scp=85065916095&partnerID=8YFLogxK

U2 - 10.1182/bloodadvances.2017014506

DO - 10.1182/bloodadvances.2017014506

M3 - Article

C2 - 29970392

AN - SCOPUS:85065916095

SN - 2473-9529

VL - 2

SP - 1551

EP - 1561

JO - Blood Advances

JF - Blood Advances

IS - 13

ER -