Versatile roles of R-Ras GAP in neurite formation of PC12 cells and embryonic vascular development

Shintaro Iwashita, Mariko Kobayashi, Yuya Kubo, Yoshimi Hinohara, Mariko Sezaki, Kenji Nakamura, Rika Suzuki-Migishima, Minesuke Yokoyama, Showbu Sato, Mitsunori Fukuda, Masayuki Ohba, Chieko Kato, Eijiro Adachi, Si Young Song

Research output: Contribution to journalArticlepeer-review

25 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)3413-3417
Number of pages5
JournalJournal of Biological Chemistry
Issue number6
Publication statusPublished - 2007 Jan 9


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