Control of the Hippo Pathway by Set7-Dependent Methylation of Yap

Methylation of nonhistone proteins is emerging as a regulatory mechanism to control protein function. Set7 (Setd7) is a SET-domain-containing lysine methyltransferase that methylates and alters function of a variety of proteins in vitro, but the in vivo relevance has not been established. We found that Set7 is a modifier of the Hippo pathway. Mice that lack Set7 have a larger progenitor compartment in the intestine, coinciding with increased expression of Yes-associated protein (Yap) target genes. Mechanistically, monomethylation of lysine 494 of Yap is critical for cytoplasmic retention. These results identify a methylation-dependent checkpoint in the Hippo pathway. [Display omitted] •Set7 binds Yap and promotes its cytoplasmic sequestration by the Hippo pathway•Methyltransferase activity of Set7 is required for proper Yap localization•Yap is monomethylated at lysine 494•Hippo signaling requires Yap K494 to induce Yap cytoplasmic localization The Hippo pathway attenuates cell growth by sequestering the transcriptional coactivator Yap in the cytoplasm. Oudhoff et al. identify a role for the methylation of Yap. Deficiency in the methyltransferase Set7 or the mutation of a single lysine residue (K494) in Yap blocks cytoplasmic sequestration and activates Yap nuclear functions.