PMID:23572525

Citation	Gupta, M, Kamynina, E, Morley, S, Chung, S, Muakkassa, N, Wang, H, Brathwaite, S, Sharma, G and Manor, D' (2013) Plekhg4 is a novel Dbl-family guanine nucleotide exchange factor for Rho-family GTPases. J. Biol. Chem. '
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 cerebellum 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. Over-expression of Plekhg4 in NIH3T3 cells induces rearrangements of the actin cytoskeleton, specifically enhanced formation of lamellopodia, fillopodia, and stress fibers. These findings indicate that Plekhg4 is a functional member of the Dbl-family of GEFs, and that the signaling pathway(s) it regulates are critical for proper cerebellar function.
Links	PubMed Online version:10.1074/jbc.M112.430371
Keywords
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
MOUSE:F8VPS6		GO:0032956: regulation of actin cytoskeleton organization	ECO:0000315:		P		Insets of fluorescent microscopy in Fig. 4 show cytoskeletal features exhibited by Plekhg4 expression, demonstrating how it plays a role in the regulation the actin cytoskeleton	complete CACAO 7969
MOUSE:F8VPS6		GO:0090630: activation of GTPase activity	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Plekhg4-GTPase association is demonstrated in Fig 3. B, and the GTPase activation by Plekhg4 is shown in Fig 3. A. Together these results demonstrate Plekhg4’s GEF function.	complete CACAO 7980
MOUSE:F8VPS6	involved_in	GO:0090630: activation of GTPase activity	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete

References

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