Plekhg4 Is a Novel Dbl Family Guanine Nucleotide Exchange Factor Protein for Rho Family GTPases

被引:29
作者
Gupta, Meghana [1 ]
Kamynina, Elena [3 ]
Morley, Samantha [2 ]
Chung, Stacey [2 ]
Muakkassa, Nora [3 ]
Wang, Hong [2 ]
Brathwaite, Shayna [2 ]
Sharma, Gaurav [3 ]
Manor, Danny [1 ,2 ]
机构
[1] Case Western Reserve Univ, Sch Med, Dept Pharmacol, Cleveland, OH 44106 USA
[2] Case Western Reserve Univ, Sch Med, Dept Nutr, Cleveland, OH 44106 USA
[3] Cornell Univ, Ithaca, NY 14853 USA
基金
美国国家卫生研究院;
关键词
DOMINANT CEREBELLAR-ATAXIA; HOMOLOGY DOMAIN; CELLULAR-TRANSFORMATION; SPINOCEREBELLAR ATAXIA; NEURITE OUTGROWTH; ONCOGENE PRODUCT; CDC42; RAC; CHAPERONE; ACTIVATION;
D O I
10.1074/jbc.M112.430371
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
Mutations in the PLEKHG4 (puratrophin-1) gene are associated with the heritable neurological disorder autosomal dominant spinocerebellar ataxia. However, the biochemical functions of this gene product have not been described. We report here that expression of Plekhg4 in the murine brain is developmentally regulated, with pronounced expression in the newborn midbrain and brainstem that wanes with age and maximal expression in the cerebellar Purkinje neurons in adulthood. We show that Plekhg4 is subject to ubiquitination and proteasomal degradation, and its steady-state expression levels are regulated by the chaperones Hsc70 and Hsp90 and by the ubiquitin ligase CHIP. On the functional level, we demonstrate that Plekhg4 functions as a bona fide guanine nucleotide exchange factor (GEF) that facilitates activation of the small GTPases Rac1, Cdc42, and RhoA. Overexpression of Plekhg4 in NIH3T3 cells induces rearrangements of the actin cytoskeleton, specifically enhanced formation of lamellopodia and fillopodia. These findings indicate that Plekhg4 is an aggregation-prone member of the Dbl family GEFs and that regulation of GTPase signaling is critical for proper cerebellar function.
引用
收藏
页码:14522 / 14530
页数:9
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