S-Space College of Medicine/School of Medicine (의과대학/대학원) Internal Medicine (내과학전공) Journal Papers (저널논문_내과학전공)
Effects of Structure of Rho GTPase-activating Protein DLC-1 on Cell Morphology and Migration
- Kim, Tai Young; Healy, Kevin D.; Der, Channing J.; Sciaky, Noah; Bang, Yung-Jue; Juliano, Rudy L.
- Issue Date
- Journal of Biological Chemistry, Vol.283 No.47, pp.32762-32770
- Actins/chemistry; Amino Acid Motifs; Cell Line; Cell Movement; Cell Shape; Focal Adhesions; GTPase-Activating Proteins/metabolism; Genes, Dominant; Humans; Models, Biological; Mutation; Protein Structure, Tertiary; Structure-Activity Relationship; Tumor Suppressor Proteins/*chemistry/physiology; rho GTP-Binding Proteins/*metabolism
- 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.
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