The Hippo-YAP pathway: new connections between regulation of organ size and cancer

Abstract

The control of organ size is a basic biological question. In the past several years, the Hippo signaling pathway has been delineated and shown to be crucial in control of organ size in both Drosophila and mammals. Acting downstream of the Hippo pathway is the Yki/YAP/TAZ transcription co-activators. In mammalian cells, the Hippo pathway kinase cascade inhibits YAP and its paralog TAZ by phosphorylation and promotion of their cytoplasmic localization. The TEAD family transcription factors have recently been identified as evolutionarily conserved key mediators of YAP biological functions. yap is a candidate oncogene, and several other components of the Hippo pathway are tumor suppressors. Dysregulation of the Hippo pathway contributes to the loss of contact inhibition observed in cancer cells. Therefore, the Hippo-YAP pathway connects the regulation of organ size and tumorigenesis.

Figure 1. The Hippo pathway in Drosophila and mammals

Corresponding components in Drosophila and mammals are shown in the same color. The abbreviations used are as follows: Ex (Expanded), Mer (Merlin, also called NF2), Hpo (Hippo), Sav (Salvador), Mats (Mob as tumor suppressor), Wts (Warts), Yki (Yorkie), Sd (Scalloped), Mst (Mst1/2, also called STK4 and STK3, Hpo homolog), WW45 (Sav homolog), Mob (Mps One Binder kinase activator-like 1A/B, MOBKL1A/B, Mats homolog), Lats (Lats1/2, Wts homolog), YAP (Yes-associated protein, Yki homolog), TAZ (transcriptional co-activator with PDZ-binding motif, also called WWTR1, Yki homolog), and TEAD (TEA domain family member 1/2/3/4). Dashed arrows indicate unknown biochemical mechanism and question marks denote unknown components.

Figure 2. A schematic view of YAP, TAZ, and Yki

YAP is a 65KDa protein with several distinct domains or motifs. It has a proline-rich (P-rich) region at the N-terminal, two tandem WW domains in the middle followed by a Src homology domain 3 binding motif (SH3 BM) PVKQPPPLAP, a coiled-coil domain (CC), and a C-terminal capped by TWL sequence, a PDZ domain ligand. The N-terminal (aa 47-154 in human YAP2, shaded in blue) of YAP was mapped to be the TEAD family transcription factors interaction domain [54], and the C-terminal of YAP (aa 292-488, shaded in pink) rich in serine, threonine, and acidic residues was shown to be a strong transcription activator [51]. The Lats phosphorylation and 14-3-3 binding critical S127 in human YAP2 and its equivalent in Yki and TAZ are also shown. The topology of Yki and TAZ are shown in similar fashion and the proteins are drawn in scale.