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 EMBO Reports show that Ser128 phosphorylation of YAP by the Nemo‐like kinase (NLK) disrupts 14‐3‐3 interactions, thereby promoting nuclear accumulation of active YAP , . Notably, Ser127‐phosphorylated YAP can be nuclear and co‐transcriptionally active upon osmotic stress, thus, challenging the dogma of YAP regulation by Ser127 phosphorylation.
See also: AW Hong et al and
S Moon et al
Organ size control in multicellular organisms is essential. During development tissues must form to the correct size, and the dimensions of adult organs must be maintained. The Hippo pathway is a pivotal regulator of tissue growth and homoeostasis by signalling through three main levels: (i) a central core cassette composed of protein kinases and scaffold adaptors, (ii) downstream regulators of diverse transcriptional programmes and (iii) upstream regulators responding to microenvironmental cues , . In Drosophila, the Hippo core cassette comprises the Hippo and Warts kinases in complex with scaffold adaptors, which inhibit the transcriptional co‐activator Yorkie through Warts‐mediated phosphorylation , . In mammals, the core consists of the MST1/2 and LATS1/2 kinases bound to adaptors, regulating the transcriptional co‐activators YAP/TAZ , , .
Upon stimulation, MST1/2 activate LATS1/2 by phosphorylation, which triggers LATS1/2‐dependent YAP phosphorylation at Ser127, Ser397 and other residues, resulting in cytoplasmic retention (due to the interaction of the protein …
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