Editors' ChoiceCell Biology

Mixed-up Hippos don’t inhibit cell growth

Sci. Signal.  05 Jul 2016:
Vol. 9, Issue 435, pp. ec154
DOI: 10.1126/scisignal.aah4597

The Hippo pathway restrains tissue growth and suppresses tumor formation by limiting the nuclear accumulation of transcriptional regulators that drive proliferative and prosurvival programs. When activated, the mammalian homologs of the kinase Hippo (MST1 and MST2) phosphorylate and activate the kinases LATS1 and LATS2, which in turn phosphorylate the transcriptional coactivators YAP and TAZ, leading to their retention in the cytoplasm and subsequent degradation. MST1 and MST2 form homodimers, and now Rawat et al. report that both transgenically expressed and endogenous MST1 and MST2 also coimmunoprecipitated as heterodimers from cultured human (HEK293) cells. Heterodimerization required the same domains of MST1 and MST2 that mediate homodimerization. Dissociation constants of complexes formed by purified proteins indicated that the formation of MST1-MST2 heterodimers was favored over the formation of MST1-MST1 or MST2-MST2 homodimers, and in vitro kinase assays demonstrated that heterodimers had less kinase activity than homodimers. Transfecting HEK293 cells with a construct encoding an activated, oncogenic form of H-RAS—a guanosine triphosphatase that mediates growth factor signaling—increased the formation of MST1-MST2 heterodimers and reduced the phosphorylation of LATS and YAP. This effect was blocked by the addition of a pharmacological inhibitor of MEK, which is one of several kinases that function downstream of RAS. Signaling through MEK to the kinase ERK promotes cell proliferation and survival. Expression of activated H-RAS in wild-type mouse embryonic fibroblasts (MEFs) and in MEFs lacking both MST1 and MST2 stimulated cellular behaviors characteristic of oncogenic transformation, such as increased proliferation and contact inhibition­–independent growth. However, expression of activated H-RAS in MEFs lacking only MST1 did not stimulate these behaviors, indicating that MST1-MST2 heterodimerization was important for H-RAS–induced transformation. Thus, the formation of MST1-MST2 heterodimers reduces the ability of the Hippo pathway to suppress cellular growth and may represent another mechanism through which RAS-MEK-ERK signaling can promote tumor formation.

S. J. Rawat, D. Araiza-Olivera, L. E. Arias-Romero, O. Villamar-Cruz, T. Y. Prudnikova, H. Roder, J. Chernoff, H-ras inhibits the Hippo pathway by promoting Mst1/Mst2 heterodimerization. Curr. Biol. 26, 1556–1563 (2016). [PubMed]