Adenomatous polyposis coli and Asef function downstream of hepatocyte growth factor and phosphatidylinositol 3-kinase.
Mutations of the tumor suppressor adenomatous polyposis coli (APC) are responsible for sporadic and familial colorectal tumors. APC negatively regulates Wnt signaling by inducing beta-catenin degradation. It has also been shown that APC plays a role in the organization of cytoskeletal networks. APC interacts with Asef and Asef2, Rac1- and Cdc42-specific guanine nucleotide exchange factors (GEFs), and stimulates their GEF activity; thereby regulating cell morphology, adhesion, and migration. Truncated mutant APCs present in colorectal tumor cells activate Asef and Asef2 constitutively and contribute to their aberrant migratory properties. We show here that hepatocyte growth factor (HGF), as well as basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF), induce the accumulation and colocalization of APC and Asef in membrane ruffles and lamellipodia of epithelial cells. Both APC and Asef were found to be required for HGF-induced cell migration. Furthermore, we show that the effects of HGF, bFGF, and EGF on APC and Asef are mediated by the activation of phosphatidylinositol 3-kinase (PI3-kinase) and require the PH domain of Asef. These results suggest that Asef and APC function downstream of HGF and PI3-kinase, and play critical roles in growth factor-mediated regulation of cell morphology and migration.
Kawasaki
Yoshihiro
Y
Laboratory of Molecular and Genetic Information, Institute for Molecular and Cellular Biosciences, The University of Tokyo, Tokyo 113, Japan.
Tsuji
Shinnosuke
S
Laboratory of Molecular and Genetic Information, Institute for Molecular and Cellular Biosciences, The University of Tokyo, Tokyo 113, Japan.
Sagara
Masaki
M
Laboratory of Molecular and Genetic Information, Institute for Molecular and Cellular Biosciences, The University of Tokyo, Tokyo 113, Japan.
Echizen
Kanae
K
Laboratory of Molecular and Genetic Information, Institute for Molecular and Cellular Biosciences, The University of Tokyo, Tokyo 113, Japan.
Shibata
Yoko
Y
Laboratory of Molecular and Genetic Information, Institute for Molecular and Cellular Biosciences, The University of Tokyo, Tokyo 113, Japan.
Akiyama
Tetsu
T
Laboratory of Molecular and Genetic Information, Institute for Molecular and Cellular Biosciences, The University of Tokyo, Tokyo 113, Japan.
D025601:Adenomatous Polyposis Coli Protein / Q000378:metabolism*; D018938:Caco-2 Cells; D002465:Cell Movement; D003599:Cytoskeleton / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D006367:HeLa Cells; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D006801:Humans; D008856:Microscopy, Fluorescence / Q000379:methods; D008954:Models, Biological; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D064067:Rho Guanine Nucleotide Exchange Factors
C576602:ARHGEF4 protein, human; D025601:Adenomatous Polyposis Coli Protein; D020662:Guanine Nucleotide Exchange Factors; D064067:Rho Guanine Nucleotide Exchange Factors; D016222:Fibroblast Growth Factor 2; D017228:Hepatocyte Growth Factor; D019869:Phosphatidylinositol 3-Kinases