Editors' ChoiceHippo Signaling

Keeping cells from getting Hippo-sized under energy stress

Sci. Signal.  28 Apr 2015:
Vol. 8, Issue 374, pp. ec108
DOI: 10.1126/scisignal.aac4217

Inhibition of the kinases in the Hippo pathway decreases the phosphorylation of Ser127 in the transcriptional coactivator YAP, which then translocates to the nucleus and, along with binding partners of the TEAD family of transcription factors, stimulates the transcriptional activation of genes involved in cellular proliferation. Wang et al. and Mo et al. showed that the transcriptional regulatory activity of YAP was inhibited by AMPK, a kinase that is activated by low cellular energy status (a high AMP/ATP ratio). The phosphorylation of Ser127 in YAP and the nuclear localization of YAP were decreased in cells experiencing energy stress induced by glucose deprivation or exposure of the cells to 2-deoxy-D-glucose (2-DG), a glucose mimic that cannot be used in glycolysis. 2-DG inhibited YAP in multiple ways. 2-DG increased the activity of Lats1, the kinase that phosphorylates Ser127 in YAP, through a mechanism that may involve the GTPase Rho and the cytoskeleton (Wang et al.) or may depend on AMPK (Mo et al.). AMPK interacted with and phosphorylated YAP. Wang et al. found that AMPK phosphorylated Ser61 in YAP in cells exposed to 2-DG, a phosphorylation event that inhibited the transcriptional activity of YAP. Both groups demonstrated that AMPK also phosphorylated YAP at Ser94, a phosphorylation event that decreased the association of YAP with TEAD. Wang et al. identified TEAD-binding sites in the promoter for GLUT3, which encodes a glucose transporter, and showed a positive correlation between GLUT3 and YAP abundance in human liver and colon cancers. Mouse embryo fibroblasts (MEFs) lacking Lats1 and Lats2 form colonies in soft agar and tumors in xenograft models, and Mo et al. showed that colony formation or tumor growth were reduced by knockdown of YAP or its homolog TAZ or treatment with the AMP mimic AICAR or metformin, which activates AMPK. Thus, glucose concentrations affect YAP activity through mechanisms involving AMPK and the Hippo pathway. However, as Hariharan notes in his commentary the effect of metabolism on YAP may be more complex because YAP can also be inhibited by energy stress through an AMPK-dependent mechanism.

W. Wang, Z.-D. Xiao, X. Li, K. E. Aziz, B. Gan, R. L. Johnson, J. Chen, AMPK modulates Hippo pathway activity to regulate energy homeostasis. Nat. Cell Biol. 17, 490–499 (2015). [PubMed]

J.-S. Mo, Z. Meng, Y. C. Kim, H. W. Park, C. G. Hansen, S. Kim, D.-S. Lim, K.-L. Guan, Cellular energy stress induces AMPK-mediated regulation of YAP and the Hippo pathway. Nat. Cell Biol. 17, 500–510 (2015). [PubMed]

I. K. Hariharan, Energy stress tames the Hippo pathway. Nat. Cell Biol. 17, 362–363 (2015). [PubMed]