Model for <i>FOXO6</i> regulation of Hippo signaling in controlling growth of the head and craniofacial features.

Mammalian Ste20 family kinases Mst1 and Mst2 form an active complex with Salvador (Salv), to further phosphorylate large tumor suppressor homolog (Lats1 and Lats2) kinase. Lats1 and Lats2 bind to a scaffold protein, Mob, to further phosphorylate two transcriptional co-activator Yap and Taz. Yap and Taz are downstream Hippo signaling components and modulate the expression of genes involved in cell growth, proliferation and apoptosis. Phosphorylated Yap and Taz are retained in the cytoplasm. Unphosphorylated Yap and Taz can enter the nucleus to activate gene expression in concert with TEAD, P73, Pax3, Runx2 transcription factors and Smad and β-catenin. Pitx2 activates FoxO6 to maintain FoxO6 expression in craniofacial tissues. In this paper, we conclude that FoxO6 binds and activates Lats1 to further inhibit Yap and cell proliferation, thereby controlling head and craniofacial growth regionally.