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betaPak-interacting exchange factor-mediated Rac1 activation requires smgGDS guanine nucleotide exchange factor in basic fibroblast growth factor-induced neurite outgrowth

Cited 19 time in Web of Science Cited 18 time in Scopus
Authors
Shin, Eun-Young; Lee, Chan-Soo; Cho, Tae Goo; Kim, Young Gyu; Song, Sukgil; Juhnn, Yong-Sung; Park, Sang Chul; Manser, Ed; Kim, Eung-Gook
Issue Date
2006-09-07
Publisher
American Society for Biochemistry and Molecular Biology
Citation
J Biol Chem. 2006 Nov 24;281(47):35954-64. Epub 2006 Sep 5.
Keywords
AnimalsCell Cycle Proteins/chemistry/*physiologyCell ProliferationEnzyme ActivationFibroblast Growth Factor 2/*chemistryGreen Fluorescent Proteins/chemistryGuanine Nucleotide Exchange Factors/*chemistry/physiologyHumansModels, BiologicalNeurites/*metabolismPC12 CellsProtein-Serine-Threonine Kinases/chemistry/*physiologyRatsRecombinant Proteins/chemistryp21-Activated Kinasesrac1 GTP-Binding Protein/*metabolism
Abstract
Neuritogenesis requires active actin cytoskeleton rearrangement in which Rho GTPases play a pivotal role. In a previous study (Shin, E. Y., Woo, K. N., Lee, C. S., Koo, S. H., Kim, Y. G., Kim, W. J., Bae, C. D., Chang, S. I., and Kim, E. G. (2004) J. Biol. Chem. 279, 1994-2004), we demonstrated that betaPak-interacting exchange factor (betaPIX) guanine nucleotide exchange factor (GEF) mediates basic fibroblast growth factor (bFGF)-stimulated Rac1 activation through phosphorylation of Ser-525 and Thr-526 at the GIT-binding domain (GBD). However, the mechanism by which this phosphorylation event regulates the Rac1-GEF activity remained elusive. We show here that betaPIX binds to Rac1 via the GBD and also activates the GTPase via an associated GEF, smgGDS, in a phosphorylation-dependent manner. Notably, the Rac1-GEF activity of betaPIX persisted for an extended period of time following bFGF stimulation, unlike other Rho GEFs containing the Dbl homology domain. We demonstrate that C-PIX, containing proline-rich, GBD, and leucine zipper domains can interact with Rac1 via the GBD in vitro and in vivo and also mediated bFGF-stimulated Rac1 activation, as determined by a modified GEF assay and fluorescence resonance energy transfer analysis. However, nonphosphorylatable C-PIX (S525A/T526A) failed to generate Rac1-GTP. Finally, betaPIX is shown to form a trimeric complex with smgGDS and Rac1; down-regulation of smgGDS expression by short interfering RNA causing significant inhibition of betaPIX-mediated Rac1 activation and neurite outgrowth. These results provide evidence for a new and unexpected mechanism whereby betaPIX can regulate Rac1 activity.
ISSN
0021-9258 (Print)
Language
English
URI
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16954223

http://hdl.handle.net/10371/29639
DOI
https://doi.org/10.1074/jbc.M602399200
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College of Medicine/School of Medicine (의과대학/대학원)Dept. of Biochemistry & Molecular Biology (생화학교실)Journal Papers (저널논문_생화학교실)
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