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

• Published in: The Journal of biological chemistry Vol. 288; no. 20; pp. 14522 - 14530
• Main Authors: Gupta, Meghana, Kamynina, Elena, Morley, Samantha, Chung, Stacey, Muakkassa, Nora, Wang, Hong, Brathwaite, Shayna, Sharma, Gaurav, Manor, Danny
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 17.05.2013; American Society for Biochemistry and Molecular Biology
• Subjects: Actins - metabolism; Aggregation; Amino Acid Sequence; Animals; Ataxia; Brain - cytology; Brain - metabolism; Cerebellum; Chlorocebus aethiops; COS Cells; Cytoskeleton - metabolism; Disease Models, Animal; Escherichia coli - metabolism; Gene Expression Regulation, Enzymologic; GTPase; Guanine Nucleotide Exchange Factor (GEF); Guanine Nucleotide Exchange Factors - genetics; Guanine Nucleotide Exchange Factors - metabolism; Guanine Nucleotide Exchange Factors - physiology; Heat Shock Protein; Mice; Molecular Sequence Data; Mutation; Neurobiology; NIH 3T3 Cells; Pseudopodia - metabolism; Purkinje Cells - metabolism; rho GTP-Binding Proteins - metabolism; Sequence Homology, Amino Acid; Spinocerebellar Ataxias - metabolism; Ubiquitin - metabolism; Ubiquitination; Aggregation; Cerebellum; Ubiquitination; Guanine Nucleotide Exchange Factor (GEF); Ataxia; GTPase; Heat Shock Protein
• ISSN: 0021-9258; 1083-351X; 1083-351X
• DOI: 10.1074/jbc.M112.430371

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. Background: Plekhg4 is putative guanine nucleotide exchange factor associated with autosomal dominant spinocerebellar ataxia. Results: Plekhg4 is regulated by the heat shock proteins and functions as a bona fide guanine nucleotide exchange factor. Conclusion: Plekhg4 is the first RhoGEF implicated in spinocerebellar ataxia. Significance: Aberrant GTPase signaling is a novel possible mechanism underlying autosomal dominant spinocerebellar ataxia.