Gankyrin plays an essential role in Ras-induced tumorigenesis through regulation of the RhoA/ROCK pathway in mammalian cells

Jiang Hong Man, Bing Liang, Yue Xi Gu, Tao Zhou, Ai Ling Li, Tao Li, Bao Feng Jin, Bing Bai, Hai Ying Zhang, Wei Na Zhang, Wei Hua Li, Wei Li Gong, Hui Yan Li, Xue Min Zhang

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)2829-2841
Number of pages13
JournalJournal of Clinical Investigation
Volume120
Issue number8
DOIs
StatePublished - Aug 2 2010

ASJC Scopus subject areas

  • Medicine(all)

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