Hippo signaling pathway in companion animal diseases, an under investigated signaling cascade

Figures & data

Figure 1. (A) Hippo On. Upon a plethora of external signals, such as G-protein coupled receptors, cell-adhesion, and (mechano)stress, MST1/2 (mammalian homologue of Drosphilia Hippo), and SAV1 are phosphorylated upon which LATS1/2-MOB protein become phosphorylated. This leads to phosphorylation of YAP/TAZ, that upon binding to 14-3-3 proteins degrades. (B) Hippo OFF. Due to lack of stimuli on MST1/2-SAV1, these protein remain unphosphorylated, as well as downstream proteins LATS1/2-MOB and YAP/TAZ. Unphosphorylated YAP/TAZ can enter the nucleus where, upon interaction ioth TEAD dries the transcription of specific gene products, such as cyr61, ctgf and nuak2.

Table 1. Drug affecting YAP/TAZ-activation.

Drug name	Mechanism(s) of action	Effect(s)	Materials & Methods	References
Verteporfin	Increasing 14-3-3 proteins in the cytosol, trapping YAP in the cytosol and therefore inhibiting of association of YAP and TEAD in the nucleus	Suppression of cancer growth because of decreased CYR61 and CTGF levels	Human tissue In vitro canine mammary gland tissue	(Mohseni et al. 2019; Zhang et al. 2018) (Zhang et al. 2016)
Carvacrol	Reducing YAP/TAZ levels in the cell and inhibiting gene expression of TAZ	Decreased fibrosis development	In vivo rats with tetrachloride-induced liver fibrosis	(Mohseni et al. 2019)
Oroxylin	Modulating HIF-1alpha, suppression nuclear translocation of YAP	Inhibited tumor invasion and migration, induction of apoptosis and inhibition of angiogenesis in liver sinusoidal endothelial cells	In vivo male ICR mice with induced liver fibrosis	(Zhang et al. 2018)
ω-3 PUFAs	Promoting YAP/TAZ degradation	Inhibition of proliferation of hepatic stellate cells and activation of hepatic stellate cells	In vivo mice with tetrachloride-induced liver fibrosis	(Zhang et al. 2016)
Dihydrotanshinone I	Blocking nuclear translocation of YAP with significant CTGF downregulation	Stimulation of autophagic flux and promotion of degradation of liver collagen	In vivo rats subjected to bile duct ligation & in vitro human and rat hepatic stellate cell line	(Ge et al. 2017)
Dihydrexidine (Dopamine agonist)	Elevating cAMP through Dopamine receptors promoting YAP phosphorylation and downregulating CTGF	Reduction of extracellular matrix stiffness and cross-linking, contractile myofibroblast function and proliferation	In vitro hepatic stellate cells In vivo eight-week-old female and male C57BL/6 mice and transgenic mice	(Haak at al. 2019)

Mohseni R, Karimi J, Tavilani H, Khodadadi I, Hashemnia M. 2019. Carvacrol ameliorates the progression of liver fibrosis through targeting of Hippo and TGF-β signaling pathways in carbon tetrachloride (CCl4)-induced liver fibrosis in rats. Immunopharm Immunotox. 41(1):163–171.

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Zhang C, Bian M, Chen X, Jin H, Zhao S, Yang X, Shao J, Chen A, Guo Q, Zhang F, et al. 2018. Oroxylin A prevents angiogenesis of LSECs in liver fibrosis via inhibition of YAP/HIF‐1α signaling. J Cell Biochem. 119(2):2258–2268.

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Zhang K, Chang Y, Shi Z, Han X, Han Y, Yao Q, Hu Z, Cui H, Zheng L, Han T, et al. 2016. ω-3 PUFAs ameliorate liver fibrosis and inhibit hepatic stellate cells proliferation and activation by promoting YAP/TAZ degradation. Sci Rep. 6:30029.

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Ge M, Liu H, Zhang Y, Li N, Zhao S, Zhao W, Zhen Y, Yu J, He H, Shao R‐g. 2017. The anti-hepatic fibrosis effects of dihydrotanshinone I are mediated by disrupting the yes-associated protein and transcriptional enhancer factor D2 complex and stimulating autophagy. Br J Pharmacol. 174(10):1147–1160.

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