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Effects of structure of Rho GTPase-activating protein DLC-1 on cell morphology and migration.

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.

SUBMITTER: Kim TY

PROVIDER: S-EPMC2583296 | biostudies-literature | 2008 Nov

REPOSITORIES: biostudies-literature

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Effects of structure of Rho GTPase-activating protein DLC-1 on cell morphology and migration.

Kim Tai Young TY Healy Kevin D KD Der Channing J CJ Sciaky Noah N Bang Yung-Jue YJ Juliano Rudy L RL

The Journal of biological chemistry 20080911 47

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 ...[more]

PMID: 18786931

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Project description:BackgroundRho GTPase-activating protein 11A (ARHGAP11A) is a member of the Rho GTPase-activating protein (RhoGAP) subfamily. However, its expression, prognostic significance and clinicopathologic factors correlation in lung adenocarcinoma is still unclear.MethodsThe original gene expression profile, survival data, and clinical information of patients with lung adenocarcinoma (LUAD) were downloaded from The Cancer Genome Atlas (TCGA) database. The expression difference of ARHGAP11A between LUAD tissues and adjacent normal tissues in the TCGA database was analyzed by using R software, and verified by the Oncomine database and immunohistochemical (IHC) assay of LUAD sections. Logistic regression was applied to analyze the relationship between the expression of ARHGAP11A and clinicopathological factors of LUAD. Kaplan-Meier (KM) survival curves and a Cox proportional-hazards model were selected to evaluate the prognostic significance of ARHGAP11A expression. Gene set enrichment analysis (GSEA) software was applied to screen the tumor signaling pathways associated with the low and high expression group of ARHGAP11A in LUAD.ResultsThe TCGA database showed that the expression of ARHGAP11A was significantly higher in LUAD tissues than in normal tissues (P<0.001). The up-regulation of ARHGAP11A in LUAD was verified by the Oncomine database (P<0.001) and IHC assay (P<0.001). Logistic regression analysis revealed the high expression of ARHGAP11A to be closely related to age, sex, advanced pathological stage, advanced T stage, and lymph node metastasis. The KM plots based on the TCGA and KM plotter databases indicated that patients with LUAD highly expressing ARHGAP11A had a poorer overall survival (OS) than patients with low expression of ARHGAP11A. Multivariate Cox regression analysis showed that the high expression of ARHGAP11A could be an important independent predictor of a poor prognosis of LUAD [hazards ratio (HR) =1.385; P<0.001]. GSEA indicated that 10 signal pathways were significantly enriched in LUAD samples with the ARHGAP11A expression phenotype.ConclusionsARHGAP11A may play a carcinogenic role in the malignant progression of LUAD, and it can be considered as a new independent prognostic factor and potential therapeutic target for LUAD.

Dataset Information

Effects of structure of Rho GTPase-activating protein DLC-1 on cell morphology and migration.

Publications

Effects of structure of Rho GTPase-activating protein DLC-1 on cell morphology and migration.

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