Complexity of Fbxw7-mediated activation of Hippo pathway Go Yoshida, Tokyo Medical and Dental University 19 November 2014 It has been recently demonstrated that the maintenance of Fbxw7 expression contributes to the inhibition of malignant phenotype of hepatic cancer cells. YAP-mediated apoptosis or cell cycle arrest might prevent the emergence and clonal expansion of hepatic cells with malignant potential (Molecular Cancer 2014, 13:110). Nakayama et al. have reported that loss of Fbxw7 increases the stabilization of transcriptional factors regulating lipid metabolism such as SREBP1 and SREBP2 as well as proteins related to proliferation such as CyclinE, c-Myc, and c-Jun (J Clin Invest. 2011;121:342–354). Metabolic reprogramming due to accumulation of SREBP family in the nucleus due to the lack of Fbxw7 non-alcoholic fatty liver disease (NAFLD), which has attracted clinical attention as precursor lesion of hepatic cancer (Nature Reviews Gastroenterology and Hepatology 2013;10, 656-665). Furthermore, Hippo pathway characterized by YAP maintains the polarity of epithelial cells. Numerous proteins localized in apical lumen have been identified as the upstream regulators of the Hippo pathway, leading to the concept that an apical multi-molecular complex affects the core kinase activity and promotes the YAP inactivation. (Biochem J. 2011;436:213-24) . YAP promotes the cell competition and distant metastasis in a manner that is highly dependent on the TEAD-interaction domain (Proc Natl Acad Sci U S A. 2012; 109: E2441–E2450). Still, cell competition-induced tumor progression and metastasis have long been believed to be mainly regulated by c-Myc, also stabilized by Fbxw7 (Nature. 2013;500:39-44). That is why the malignant cases of hepatic cancer cannot be attributable only to the activated Hippo pathway due to loss-of-functional mutated Fbxw7 or epigenetically-silenced Fbxw7. Competing interests No Competing Interests Exist.