Regulation of a DLK-1 and p38 MAP kinase pathway by the ubiquitin ligase RPM-1 is required for presynaptic development

被引:271
作者
Nakata, K
Abrams, B
Grill, B
Goncharov, A
Huang, X
Chisholm, AD
Jin, YS [1 ]
机构
[1] Univ Calif Santa Cruz, Dept Mol Cell & Dev Biol, Santa Cruz, CA 95064 USA
[2] Univ Calif Santa Cruz, Howard Hughes Med Inst, Santa Cruz, CA 95064 USA
基金
美国国家卫生研究院; 日本学术振兴会;
关键词
D O I
10.1016/j.cell.2004.12.017
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Synapses display a stereotyped ultrastructural organization, commonly containing a single electron-dense presynaptic density surrounded by a cluster of synaptic vesicles. The mechanism controlling subsynaptic proportion is not understood. Loss of function in the C. elegans rpm-1 gene, a putative RING finger/E3 ubiquitin ligase, causes disorganized presynaptic cytoarchitecture. RPM-1 is localized to the presynaptic periactive zone. We report that RPM-1 negatively regulates a p38 MAP kinase pathway composed of the dual leucine zipper-bearing MAPKKK DLK-1, the MAPKK MKK-4, and the p38 MAP kinase PMK-3. Inactivation of this pathway suppresses rpm-1 loss of function phenotypes, whereas overexpression or constitutive activation of this pathway causes synaptic defects resembling rpm-1(lf) mutants. DLK-1, like RPM-1, is localized to the periactive zone. DLK-1 protein levels are elevated in rpm-1 mutants. The RPM-1 RING finger can stimulate ubiquitination of DLK-1. Our data reveal a presynaptic role of a previously unknown p38 MAP kinase cascade.
引用
收藏
页码:407 / 420
页数:14
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