title: Gankyrin plays an essential role in Ras-induced tumorigenesis through regulation of the RhoA/ROCK pathway in mammalian cells.
abstract: Activating mutations in Ras proteins are present in about 30% of human cancers. Despite tremendous progress in the study of Ras oncogenes, many aspects of the molecular mechanisms underlying Ras-induced tumorigenesis remain unknown. Through proteomics analysis, we previously found that the protein Gankyrin, a known oncoprotein in hepatocellular carcinoma, was upregulated during Ras-mediated transformation, although the functional consequences of this were not clear. Here we present evidence that Gankyrin plays an essential role in Ras-initiated tumorigenesis in mouse and human cells. We found that the increased Gankyrin present following Ras activation increased the interaction between the RhoA GTPase and its GDP dissociation inhibitor RhoGDI, which resulted in inhibition of the RhoA effector kinase Rho-associated coiled coil-containing protein kinase (ROCK). Importantly, Gankyrin-mediated ROCK inhibition led to prolonged Akt activation, a critical step in activated Ras-induced transformation and tumorigenesis. In addition, we found that Gankyrin is highly expressed in human lung cancers that have Ras mutations and that increased Gankyrin expression is required for the constitutive activation of Akt and tumorigenesis in these lung cancers. Our findings suggest that Gankyrin is a key regulator of Ras-mediated activation of Akt through inhibition of the downstream RhoA/ROCK pathway and thus plays an essential role in Ras-induced tumorigenesis.
authors.affiliation: State Key Laboratory of Proteomics, Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing, China.
authors.forename: Jiang-Hong
authors.initials: JH
authors.lastname: Man
authors.forename: Bing
authors.initials: B
authors.lastname: Liang
authors.forename: Yue-Xi
authors.initials: YX
authors.lastname: Gu
authors.forename: Tao
authors.initials: T
authors.lastname: Zhou
authors.forename: Ai-Ling
authors.initials: AL
authors.lastname: Li
authors.forename: Tao
authors.initials: T
authors.lastname: Li
authors.forename: Bao-Feng
authors.initials: BF
authors.lastname: Jin
authors.forename: Bing
authors.initials: B
authors.lastname: Bai
authors.forename: Hai-Ying
authors.initials: HY
authors.lastname: Zhang
authors.forename: Wei-Na
authors.initials: WN
authors.lastname: Zhang
authors.forename: Wei-Hua
authors.initials: WH
authors.lastname: Li
authors.forename: Wei-Li
authors.initials: WL
authors.lastname: Gong
authors.forename: Hui-Yan
authors.initials: HY
authors.lastname: Li
authors.forename: Xue-Min
authors.initials: XM
authors.lastname: Zhang
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic; D011905:Genes, ras; D020730:Guanine Nucleotide Dissociation Inhibitors / Q000502:physiology; D006801:Humans; D008175:Lung Neoplasms / Q000209:etiology*; D051379:Mice; D041681:NIH 3T3 Cells; D051059:PTEN Phosphohydrolase / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000502:physiology*; D020741:rho GTP-Binding Proteins / Q000502:physiology*; D062948:rho Guanine Nucleotide Dissociation Inhibitor alpha; D054460:rho-Associated Kinases / Q000502:physiology*; D062947:rho-Specific Guanine Nucleotide Dissociation Inhibitors; D020742:rhoA GTP-Binding Protein
chemical_list: C569638:ARHGDIA protein, human; D020730:Guanine Nucleotide Dissociation Inhibitors; D014157:Transcription Factors; C525549:gankyrin protein, mouse; D062948:rho Guanine Nucleotide Dissociation Inhibitor alpha; D062947:rho-Specific Guanine Nucleotide Dissociation Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D054460:rho-Associated Kinases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; C526380:RhoA protein, mouse; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein