title: Versatile roles of R-Ras GAP in neurite formation of PC12 cells and embryonic vascular development.
abstract: Ras GTPase-activating proteins (GAP) are negative regulators of Ras that convert active Ras-GTP to inactive Ras-GDP. R-Ras GAP is a membrane-associated molecule with stronger GAP activity for R-Ras, an activator of integrin, than H-Ras. We found that R-Ras GAP is down-regulated during neurite formation in rat pheochromocytoma PC12 cells by nerve growth factor (NGF), which is blocked by the transient expression of R-Ras gap or dominant negative R-ras cDNA. By establishing a PC12 subclone that stably expresses exogenous R-Ras GAP, it was found that NGF reduced endogenous R-Ras GAP but not exogenous R-Ras GAP, suggesting that down-regulation of R-Ras GAP occurs at the transcription level. To clarify the physiological role of R-Ras GAP, we generated mice that express mutant Ras GAP with knocked down activity. While heterozygotes are normal, homozygous mice die at E12.5-13.5 of massive subcutaneous and intraparenchymal bleeding, probably due to underdeveloped adherens junctions between capillary endothelial cells. These results show essential roles of R-Ras GAP in development and differentiation: its expression is needed for embryonic development of blood vessel barriers, whereas its down-regulation facilitates NGF-induced neurite formation of PC12 cells via maintaining activated R-Ras.
authors.affiliation: Mitsubishi Kagaku Institute of Life Sciences (MITILS), Machida, Tokyo 194-8511, Japan.
authors.forename: Shintaro
authors.initials: S
authors.lastname: Iwashita
authors.forename: Mariko
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Yuya
authors.initials: Y
authors.lastname: Kubo
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Hinohara
authors.forename: Mariko
authors.initials: M
authors.lastname: Sezaki
authors.forename: Kenji
authors.initials: K
authors.lastname: Nakamura
authors.forename: Rika
authors.initials: R
authors.lastname: Suzuki-Migishima
authors.forename: Minesuke
authors.initials: M
authors.lastname: Yokoyama
authors.forename: Showbu
authors.initials: S
authors.lastname: Sato
authors.forename: Mitsunori
authors.initials: M
authors.lastname: Fukuda
authors.forename: Masayuki
authors.initials: M
authors.lastname: Ohba
authors.forename: Chieko
authors.initials: C
authors.lastname: Kato
authors.forename: Eijiro
authors.initials: E
authors.lastname: Adachi
authors.forename: Si-Young
authors.initials: SY
authors.lastname: Song
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D015536:Down-Regulation / Q000235:genetics; D006470:Hemorrhage / Q000196:embryology* / Q000235:genetics / Q000503:physiopathology*; D051379:Mice; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000235:genetics; D016501:Neurites / Q000378:metabolism* / Q000502:physiology; D016716:PC12 Cells; D051381:Rats; D020703:ras GTPase-Activating Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000172:deficiency / Q000502:physiology*
chemical_list: D020703:ras GTPase-Activating Proteins