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The Hippo pathway (known as Salvador-Warts-Hippo pathway) was first discovered to be involved in controlling tissue growth in Drosophila melanogaster, and it has recently emerged as a vital tumor-suppressor network. The Hippo pathway is a highly evolutionarily conserved pathway that controls a variety of functions that are crucial to several carcinogenesis processes, including proliferation, apoptosis, and stem cell maintenance, etc.
The core of the mammalian Hippo pathway is composed of a protein complex that includes kinases MST1 and MST2, large tumor suppressors 1 and 2 (LATS1 and LATS2), adaptor proteins Salvador homolog 1 (SAV1) and MOB kinase activator 1A and 1B (MOB1A and MOB1B). MST1 and MST2 facilitate LATS1 and LATS2 phosphorylation, in turn, which facilitates LATS-dependent phosphorylation of the homologous oncoproteins YAP and TAZ (PDZ-binding motif). When the Hippo pathway is active, its main effectors, YAP and TAZ, are phosphorylated through the Hippo core complex and retained in the cytoplasm where they undergo proteasomal degradation. When the Hippo pathway is suppressed or inactive, YAP and TAZ translocate to the nucleus. In the nucleus, they regulate the activity of many transcription factors involved in cell proliferation, survival, metastases development, microRNA processing, and stem cell maintenance such as TEADs, SMADs, TBX5, and RUNT1, 2 and p73. On the basis of this action mechanism, Hippo effectors YAP and TAZ can play either as tumor suppressors when located in the cytoplasm or as oncogenes through facilitating transcriptional activation in the nucleus (Figure 1).
Figure 1. The Hippo signaling pathway and main regulators.
Mutations in Hippo pathway components have been linked to many human diseases. Besides Mer/NF2 as the tumor suppressor underlying Neurofibromatosis 2, a heterozygous missense mutation in TEAD1, Y421H, was identified in two independent pedigrees as the cause of Sveinsson’s chorioretinal atrophy (SCRA). The YAP/TAZ-TEAD transcription factor complex represents a common target of oncogenic transformation. Amplification of the YAP gene locus has been reported at varying frequencies in a broad spectrum of human and murine tumors, such as oral squamous-cell carcinomas, and carcinomas of the liver, lung, pancreas, esophagus, and mammary gland. In one study focusing on mammary tumors, TAZ overexpression was detected in 21% of primary breast cancers. This study further indicated that TAZ may govern the invasiveness of breast cancer cells. Consistent with these findings, overexpression of YAP or TAZ can induce anchorage-independent growth and EMT of immortalized mammary and pancreatic epithelial cells in vitro. In addition, the YAP/TAZ partner TEAD4 has also been reported to be amplified in multiple cancers, and TEAD4 alone promoted anchorage-independent growth of MCF10A cells in vitro.
Currently, the YAP/TAZ-TEADs transcription complex has been the most attractive anti-cancer targets in the Hippo pathway. A screen of 3,300 drugs suggested that members of the Porphyrin family, including Hematoporphyrin (HP), Verteporfin (VP), and Protoporphyrin IV, significantly suppress the formation of YAP-TEADs complex. Furthermore, VP exerts significantly inhibitory effects on cell proliferation and chemotherapy resistance, and restores sensitivity to cisplatin and erlotinib. Zhang et al. found that Vestigial-like (VGLL) 4 directly competes with YAP in binding to TEADs, thus disrupting the YAP-TEADs interaction. A peptide mimicking the function of VGLL4 exerts an obvious inhibitory effect on tumor growth in vivo and in vitro. In addition, several studies found that dobutamine, a β-adrenergic receptor agonist, attenuates YAP-dependent transcription through directly inducing the phosphorylated YAP expression in the cytosol. These studies revealed that disruption of downstream transcription complexes may be a promising therapeutic approach. Consequently, drugs targeting the key proteins or factors in this network could also be a potential strategy for cancer treatment.
Hippo Signaling Pathway Product Panel
| ACTG1 | AJUBA | AXIN1 | BIRC2 | BMP2 | BMPR1A |
| CCND1 | CCND3 | CDH1 | CSNK1D | CSNK1E | CTNNA1 |
| CTNNB1 | GSK3B | LATS1 | LATS2 | MOB1A | MYC |
| NF2 | PPP1CC | PPP2R1B | PPP2R2B | PRKCI | PRKCZ |
| SCRIB | SMAD2 | SMAD3 | TCF7L2 | TEAD4 | TGFB1 |
| TGFBR2 | TP53BP2 | YAP1 | YWHAG | CCND1 | PPP1CC |
| PRKCZ |
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