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Effects of Structure of Rho GTPase-activating Protein DLC-1 on Cell Morphology and Migration

Cited 44 time in Web of Science Cited 48 time in Scopus
Authors
Kim, Tai Young; Healy, Kevin D.; Der, Channing J.; Sciaky, Noah; Bang, Yung-Jue; Juliano, Rudy L.
Issue Date
2008-11
Publisher
American Society for Biochemistry and Molecular Biology
Citation
Journal of Biological Chemistry, Vol.283 No.47, pp.32762-32770
Keywords
Actins/chemistryAmino Acid MotifsCell LineCell MovementCell ShapeFocal AdhesionsGTPase-Activating Proteins/metabolismGenes, DominantHumansModels, BiologicalMutationProtein Structure, TertiaryStructure-Activity RelationshipTumor Suppressor Proteins/*chemistry/physiologyrho GTP-Binding Proteins/*metabolism
Abstract
DLC-1 encodes a Rho GTPase-activating protein (RhoGAP) and negative regulator of specific Rho family proteins (RhoA-C and Cdc42). DLC-1 is a multi-domain protein, with the RhoGAP catalytic domain flanked by an amino-terminal sterile alpha motif (SAM) and a carboxyl-terminal START domain. The roles of these domains in the regulation of DLC-1 function remain to be determined. We undertook a structure-function analysis involving truncation and missense mutants of DLC-1. We determined that the amino-terminal SAM domain functions as an autoinhibitory domain of intrinsic RhoGAP activity. Additionally, we determined that the SAM and START domains are dispensable for DLC-1 association with focal adhesions. We then characterized several mutants for their ability to regulate cell migration and identified constitutively activated and dominant negative mutants of DLC-1. We report that DLC-1 activation profoundly alters cell morphology, enhances protrusive activity, and can increase the velocity but reduce directionality of cell migration. Conversely, the expression of the amino-terminal domain of DLC-1 acts as a dominant negative and profoundly inhibits cell migration by displacing endogenous DLC-1 from focal adhesions.
ISSN
0021-9258
Language
English
URI
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18786931

http://www.jbc.org/content/283/47/32762.full.pdf

https://hdl.handle.net/10371/45971
DOI
https://doi.org/10.1074/jbc.M800617200
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College of Medicine/School of Medicine (의과대학/대학원)Internal Medicine (내과학전공)Journal Papers (저널논문_내과학전공)
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