title: Plekhg4 is a novel Dbl family guanine nucleotide exchange factor protein for rho family GTPases.
abstract: 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.
authors.affiliation: Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106.
authors.forename: Meghana
authors.initials: M
authors.lastname: Gupta
authors.affiliation: Cornell University, Ithaca, New York 14853.
authors.forename: Elena
authors.initials: E
authors.lastname: Kamynina
authors.affiliation: Department of Nutrition, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106.
authors.forename: Samantha
authors.initials: S
authors.lastname: Morley
authors.affiliation: Department of Nutrition, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106.
authors.forename: Stacey
authors.initials: S
authors.lastname: Chung
authors.affiliation: Cornell University, Ithaca, New York 14853.
authors.forename: Nora
authors.initials: N
authors.lastname: Muakkassa
authors.affiliation: Department of Nutrition, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106.
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Nutrition, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106.
authors.forename: Shayna
authors.initials: S
authors.lastname: Brathwaite
authors.affiliation: Cornell University, Ithaca, New York 14853.
authors.forename: Gaurav
authors.initials: G
authors.lastname: Sharma
authors.affiliation: Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106; Department of Nutrition, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106. Electronic address: dxm178@case.edu.
authors.forename: Danny
authors.initials: D
authors.lastname: Manor
mesh_terms: D000199:Actins / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism; D019556:COS Cells; D002522:Chlorocebus aethiops; D003599:Cytoskeleton / Q000378:metabolism; D004195:Disease Models, Animal; D004926:Escherichia coli / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D041681:NIH 3T3 Cells; D011554:Pseudopodia / Q000378:metabolism; D011689:Purkinje Cells / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D020754:Spinocerebellar Ataxias / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism*
chemical_list: D000199:Actins; D020662:Guanine Nucleotide Exchange Factors; C512843:Mcf2 protein, mouse; C582673:PLEKHG4 protein, mouse; D025801:Ubiquitin; D020741:rho GTP-Binding Proteins
keywords: Aggregation; Ataxia; Cerebellum; GTPase; Guanine Nucleotide Exchange Factor (GEF); Heat Shock Protein; Ubiquitination