Snapshots of a hybrid transcription factor in the Hippo pathway

Abstract

The Hippo pathway plays key roles in animal development. It suppresses tumorigenesis by controlling the transcription of the target genes that are critical for cell proliferation and apoptosis. The transcriptional coactivator YAP is the major downstream effector of the Hippo signaling. Upon extracellular stimulation, a kinase cascade in the Hippo pathway phosphorylates YAP and promotes its cytoplasmic sequestration by 14-3-3 and ubiquitin-dependent degradation. When the Hippo pathway is turned off, YAP (which lacks a DNA-binding domain) is dephosphorylated and translocates to the nucleus, where it associates with the transcription factor TEAD to form a functional heterodimeric transcription factor and to promote the expression of the Hipporesponsive genes. Recently, structures of the YAPbinding domain of TEAD alone or in complex with YAP have revealed the atomic details of the TEAD-YAP interaction. Here, I review these exciting advances, propose a strategy for targeting the TEAD-YAP interaction using small molecules, and suggest potential mechanisms by which phosphorylation and 14-3-3 binding regulate the cytoplasmic retention of YAP.

A Novel NHERF1 Mutation in Human Breast Cancer and Effects on Malignant Progression

“…In this study, we found NHERF1 A190D mutation also appears to affect YAP function. The phosphorylation of YAP at serine 127 residue promotes its binding to 14-3-3 and impairs the nuclear import of YAP (37)(38)(39). NHERF1 A190D mutation led to a decrease in YAP phosphorylation.…”

Structural Basis for Autoactivation of Human Mst2 Kinase and Its Regulation by RASSF5

“…Although YAP does not contain a DNA-binding domain, it binds to the TEAD family of transcription factors (which contains a sequence-specific DNA-binding domain) to form a functional hybrid transcription factor (Luo, 2010; Sudol et al, 2012; Zhao et al, 2008). The YAP–TEAD hybrid then activates the transcription of Hippo-responsive genes that promote cell growth and proliferation and inhibit apoptosis.…”

Structural basis for Mob1-dependent activation of the core Mst–Lats kinase cascade in Hippo signaling

“…YAP is a major downstream effector of the Hippo pathway. It associates with the TEAD family of transcription factors to stimulate the transcription of Hippo-responsive genes that promote cell proliferation and inhibit apoptosis (Zhao et al 2008b;Luo 2010;Sudol et al 2012). Lats1/2-mediated phosphorylation inhibits YAP by promoting its cytoplasmic sequestration (Dong et al 2007;Zhao et al 2007;Hao et al 2008) and ubiquitination-dependent degradation (Zhao et al 2010b), thereby inhibiting the expression of Hippo-responsive genes, halting proliferation, and promoting apoptosis.…”