RasGRP1 is required for human NK cell function.
Cross-linking of NK activating receptors activates phospholipase-gamma and subsequently induces diacylglycerol and Ca(2+) as second messengers of signal transduction. Previous studies reported that Ras guanyl nucleotide-releasing protein (RasGRP) 1, which is activated by diacylglycerol and Ca(2+), is crucial for TCR-mediated Ras-ERK activation. We now report that RasGRP1, which can also be detected in human NK cells, plays an essential role in NK cell effector functions. To examine the role of RasGRP1 in NK cell functions, the expression of RasGRP1 was suppressed using RNA interference. Knockdown of RasGRP1 significantly blocked ITAM-dependent cytokine production as well as NK cytotoxicity. Biochemically, RasGRP1-knockdown NK cells showed markedly decreased ability to activate Ras, ERK, and JNK. Activation of the Ras-MAPK pathway was independently shown to be indispensable for NK cell effector functions via the use of specific pharmacological inhibitors. Our results reveal that RasGRP1 is required for the activation of the Ras-MAPK pathway leading to NK cell effector functions. Moreover, our data suggest that RasGRP1 might act as an important bridge between phospholipase-gamma activation and NK cell effector functions via the Ras-MAPK pathway.
Lee
Suk Hyung
SH
Cell Therapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Yuseong-gu, Daejeon, Republic of Korea.
Yun
Sohyun
S
Lee
Jiwon
J
Kim
Mi Jeong
MJ
Piao
Zheng-Hao
ZH
Jeong
Mira
M
Chung
Jin Woong
JW
Kim
Tae-Don
TD
Yoon
Suk Ran
SR
Greenberg
Philip D
PD
Choi
Inpyo
I
D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D005312:Fetal Blood / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007424:Intracellular Fluid / Q000276:immunology / Q000378:metabolism; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D014470:Umbilical Cord / Q000098:blood supply / Q000166:cytology / Q000276:immunology
D004268:DNA-Binding Proteins; D020662:Guanine Nucleotide Exchange Factors; C491790:RASGRP1 protein, human