YAP needs Nemo to guide a Hippo.

The Hippo growth control pathway coordinates cell proliferation, death, differentiation and stemness through regulatory phosphorylation of the YAP proto‐oncoprotein, a major nuclear effector of Hippo signalling. In particular, YAP phosphorylation on Ser127 can promote inhibitory 14‐3‐3 interactions and cytoplasmic sequestration. Two studies in this issue of show that Ser128 phosphorylation of YAP by the Nemo‐like kinase (NLK) disrupts 14‐3‐3 interactions, thereby promoting nuclear accumulation of active YAP 1, 2. Notably, Ser127‐phosphorylated YAP can be nuclear and co‐transcriptionally active upon osmotic stress, thus, challenging the dogma of YAP regulation by Ser127 phosphorylation.