Hippo pathway: Regulation, deregulation and potential therapeutic targets in cancer

Abstract

Hippo pathway is a master regulator of development, cell proliferation, stem cell function, tissue regeneration, homeostasis, and organ size control. Hippo pathway relays signals from different extracellular and intracellular events to regulate cell behavior and functions. Hippo pathway is conserved from Protista to eukaryotes. Deregulation of the Hippo pathway is associated with numerous cancers. Alteration of the Hippo pathway results in cell invasion, migration, disease progression, and therapy resistance in cancers. However, the function of the various components of the mammalian Hippo pathway is yet to be elucidated in detail especially concerning tumor biology. In the present review, we focused on the Hippo pathway in different model organisms, its regulation and deregulation, and possible therapeutic targets for cancer treatment.

Keywords: Cancer metabolism; Epigenetics; Hippo pathway; Immunity; Regulation.

Figure 1:. Components of the Hippo pathway in Drosophila/Mammals, C. elegans and Yeast (S. cerevisiae):

In Drosophila/Mammals (left figure), together with Sav/SAV1 and Mats/MOB1, the Hippo/MST1/2 (kinase) phosphorylates and activates Warts/LATS1/2 (kinase) that in turn phosphorylates and inactivates Yki/YAP/TAZ (downstream effector). Inactivation of hippo pathway results in Yki/YAP/TAZ nuclear translocation and interaction with Sd/TEAD or other transcription factors to induce target gene expression. In C. elegans (middle figure), the role of upstream regulator CST1/2 (Hippo homolog) on the activation of F09A5.4 (Putative Mats homolog), SAV1 (Salvador homolog) and WTS-1 (Warts homolog) is unknown. However, the WTS-1_YAP-1_EGL-44 axis is conserved, supported by the same role as Warts_Yorkie_Scalloped or LATS_YAP_TEAD axis of Hippo pathway. In Yeast (S. cerevisiae), mitotic exit network (MEN) is similar to canonical LATS pathway (Salvador/warts/Hippo system), whereas RAM network is similar to non-canonical NDR pathway (furry/tricomered/Hippo system). The core components of MEN include, Cdc15 (MST/Hippo -related kinase domain), and the protein kinases Dbf2 and Dbf20 (Paralogous protein LATS-family kinases) and Mob1 (co-activator). The core components of RAM network include Kic1 (MST/Hippo related protein kinase), Cbk1 (Ndr/LATS family-related protein kinase), Tao3 (scaffold protein), Mob2, and Hym1 (activator), Ace2 and Ssd1 (downstream effectors).

Figure 2:. Regulatory domains of YAP/TAZ (Hippo pathway effector proteins):

Domains of YAP effector include the Proline-rich domain (P-rich), TEAD binding domain (TEAD BD), two WW domain, SH3-binding domain, coiled-coil domain (CC), transcriptional activation domain (TAD) and PDZ-binding motif. TAZ has TEAD binding domain (TEAD BD), one WW domain, coiled-coil domain (CC), transcriptional activation domain (TAD), and PDZ-binding motif.

Figure 3:. Regulators and downstream targets of the Hippo pathway:

The figure shows upstream activators and inhibitors of the Mammalian Hippo pathway, their binding partners and downstream target genes. Apical polarity complex (Crumbs complex) and basal polarity complex (Scribble complex) as well as cell adhesion molecules such as E-cadherin and signaling molecules positively regulate Hippo pathway (Left side of the figure), whereas, PAR complex and various signaling molecules negatively regulate Hippo pathway (Right side of the figure). These upstream regulators regulate nuclear translocation and binding of YAP/TAZ with different transcription factors that induce expression of genes involved in cell proliferation and migration, stemness, differentiation, apoptosis, DNA damages response etc.