title: ARHGAP18, a GTPase-activating protein for RhoA, controls cell shape, spreading, and motility.
abstract: Rho GTPases are molecular switches that transmit biochemical signals in response to extracellular stimuli to elicit changes in the actin cytoskeleton. Rho GTPases cycle between an active, GTP-bound state and an inactive, GDP-bound state. These states are regulated by two distinct families of proteins-guanine nucleotide exchange factors and GTPase-activating proteins (GAPs). We studied the role of a previously uncharacterized GAP, ARHGAP18 (MacGAP). Overexpression of ARHGAP18 suppressed the activity of RhoA and disrupted stress fiber formation. Conversely, silencing of ARHGAP18 by small interfering RNA transfection-enhanced stress fiber formation and induced rounding of cells. We examined the role of ARHGAP18 in cell spreading and migration. Immunofluorescence analysis revealed that ARHGAP18 was localized to the leading edge during cell spreading and migration. ARHGAP18-knockdown cells showed impaired spreading, premature formation of stress fibers, and sustained activation of RhoA upon cell attachment. In addition, knockdown and overexpression of ARHGAP18 resulted in the inhibition and promotion of cell migration, respectively. Furthermore, ARHGAP18 was required for the polarization of cells for migration. Our results define ARHGAP18 as one of the crucial factors for the regulation of RhoA for the control of cell shape, spreading, and migration.
authors.affiliation: Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Masao
authors.initials: M
authors.lastname: Maeda
authors.forename: Hitoki
authors.initials: H
authors.lastname: Hasegawa
authors.forename: Toshinori
authors.initials: T
authors.lastname: Hyodo
authors.forename: Satoko
authors.initials: S
authors.lastname: Ito
authors.forename: Eri
authors.initials: E
authors.lastname: Asano
authors.forename: Hong
authors.initials: H
authors.lastname: Yuang
authors.forename: Kohei
authors.initials: K
authors.lastname: Funasaka
authors.forename: Kaoru
authors.initials: K
authors.lastname: Shimokata
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Hasegawa
authors.forename: Michinari
authors.initials: M
authors.lastname: Hamaguchi
authors.forename: Takeshi
authors.initials: T
authors.lastname: Senga
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D016764:Cell Polarity / Q000235:genetics; D048430:Cell Shape / Q000235:genetics; D005455:Fluorescent Antibody Technique; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D005786:Gene Expression Regulation; D020868:Gene Silencing; D006801:Humans; D010957:Plasmids; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D022502:Stress Fibers / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: C542464:ARHGAP18 protein, human; D000199:Actins; D020690:GTPase-Activating Proteins; D034741:RNA, Small Interfering; C066737:RHOA protein, human; D020742:rhoA GTP-Binding Protein