Targeting the Hippo Pathway and Cancer through the TEAD Family of Transcription Factors

Abstract

The Hippo pathway is a critical transcriptional signaling pathway that regulates cell growth, proliferation and organ development. The transcriptional enhanced associate domain (TEAD) protein family consists of four paralogous transcription factors that function to modulate gene expression in response to the Hippo signaling pathway. Transcriptional activation of these proteins occurs upon binding to the co-activator YAP/TAZ whose entry into the nucleus is regulated by Lats1/2 kinase. In recent years, it has become apparent that the dysregulation and/or overexpression of Hippo pathway effectors is implicated in a wide range of cancers, including prostate, gastric and liver cancer. A large body of work has been dedicated to understanding the therapeutic potential of modulating the phosphorylation and localization of YAP/TAZ. However, YAP/TAZ are considered to be natively unfolded and may be intractable as drug targets. Therefore, TEAD proteins present themselves as an excellent therapeutic target for intervention of the Hippo pathway. This review summarizes the functional role of TEAD proteins in cancer and assesses the therapeutic potential of antagonizing TEAD function in vivo.

Keywords: Hippo; TAZ; TEAD; YAP; cancer; transcription factor.

Figure 1

The Hippo signaling pathway is composed of neurofibromin 2 (NF2), mammalian STE20-like protein kinase 1/2 (Mst1/2) and large tumor suppressor 1/2 (Lats1/2). NF2, Mst1/2, and Lats1/2 are represented as red, orange, and brown ellipsoids, respectively. Phosphorylation of either Yes-associated protein (YAP) or transcriptional co-activator with PDZ-binding motif (TAZ) by Lats1/2 affects nuclear translocation of YAP/TAZ. Transcription of DNA can be activated by palmitoylated transcriptional enhanced associate domain (TEAD) in the presence of YAP/TAZ. The palmitate group is illustrated as a yellow line within the blue ellipsoid representing TEAD. A TEAD antagonist could serve as a useful strategy for altering the TEAD-YAP transcriptome in various cancer cells.

Figure 2

Domain organization of Hippo transcription factors TEAD, YAP (isoform YAP1-2γ), and TAZ. The percent identity for individual domains of TEAD1–4 was calculated relative to TEAD1 using Clustal Omega [13].

Figure 3

TEAD is a protein with multiple domains, which is composed of a DNA Binding Domain (DBD) and a YAP Binding Domain (YBD). (A) The DBD structure is illustrated from protein data bank ID (PDB) 5GZB and is composed of a homeodomain fold with three alpha helices (shown in green) bound to DNA (colored in grey); (B) Structural analysis of TEAD DBD using the interaction map from DNAproDB [34] illustrates the DNA major- and minor-groove protein residue contacts in cyan and pink, respectively. Nucleic acid contacts with DBD L1 loop are indicated by a blue square and contacts with DBD helix 3 are shown as red circles; (C) The YBD is post-translationally modified by palmitate (colored yellow) that extends towards the interior of YBD (colored in blue).

Figure 4

Crystal Structures of TEAD YBD (colored blue) bound to co-activator peptides from (A) YAP (orange); (B) TAZ binding mode one (gold); (C) Vgll1 (yellow); (D) TAZ binding mode two (gold and red); and (E) Vgll4 (purple). In both (D) and (E), the YBD is shown in blue and grey surface renderings since co-activators in the crystal structure induced dimerization. The TEAD binding interfaces for each co-crystal structure are labeled as 1, 2, and 3.

Figure 5

The palmitate group (colored yellow) extends towards the interior of YBD shown as a grey surface representation. The lipid pockets of (A) TEAD2 and (B) TEAD3 are identical except for the Phe/Tyr difference, which is shown in blue stick format. For TEAD3, the bulkier Tyr233 requires the lipid chain to reorient relative to the TEAD2 structure. The most noticeable reorientations are marked with red arrows on the TEAD3 lipid pocket to illustrate the alkyl chain moving down and the carbonyl group rotating out towards the solvent.