期刊
GENES TO CELLS
卷 18, 期 7, 页码 533-543出版社
WILEY-BLACKWELL
DOI: 10.1111/gtc.12054
关键词
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资金
- Ministry of Education, Culture, Science, Sports and Technology of Japan
- Uehara Memorial Foundation
- Takeda Science Foundation
- Grants-in-Aid for Scientific Research [22616001, 24770146, 24121702] Funding Source: KAKEN
LIM-kinase 1 (LIMK1) regulates actin cytoskeletal reorganization by phosphorylating and inactivating actin-depolymerizing factor and cofilin. We examined the role of LIMK1 in brain-derived neurotrophic factor (BDNF)-induced neuritogenesis in primary-cultured rat cortical neurons. Knockdown of LIMK1 or expression of a kinase-dead LIMK1 mutant suppressed BDNF-induced enhancement of primary neurite formation. By contrast, expression of an active form of LIMK1 promoted primary neuritogenesis in the absence of BDNF. BDNF-induced neuritogenesis was inhibited by KN-93, an inhibitor of Ca2+/calmodulin-dependent protein kinases (CaMKs), but not by STO-609, an inhibitor of CaMK-kinase (CaMKK). CaMKK activity is required for the activation of CaMKI and CaMKIV, but not CaMKII, which suggests that CaMKII is principally involved in BDNF-induced enhancement of neuritogenesis. Knockdown of CaMKII, but not CaMKII, suppressed BDNF-induced neuritogenesis. Active CaMKII promoted neuritogenesis, and this promotion was inhibited by knockdown of LIMK1, indicating that CaMKII is involved in BDNF-induced neuritogenesis via activation of LIMK1. Furthermore, in vitro kinase assays revealed that CaMKII phosphorylates LIMK1 at Thr-508 in the kinase domain and activates the cofilin-phosphorylating activity of LIMK1. In summary, these results suggest that CaMKII-mediated activation of LIMK1 plays a crucial role in BDNF-induced enhancement of primary neurite formation.
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