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    • br Hippo pathway signalling The Hippo

    2022-07-01


    Hippo pathway signalling The Hippo pathway is an evolutionarily conserved signal transduction pathway regulated by cell-cell contact, cell polarity, mechanical cues, ligands of G-protein coupled receptors, and cellular dpp-4 status [10]. This pathway is linked to development, cell proliferation, cell shape and growth [11], as well as tissue regeneration and stem cell regulation [12]. Moreover, the Hippo pathway has also been implicated in regulating cancer immunity, innate immune responses against pathogens, and autoimmune diseases (for details see review from [13]). The origin and discovery of the Hippo pathway began in 1995 with Drosophila melanogaster. Justice and colleagues using a Drosophila model identified a new tumor suppressor gene, warts (wts) (also referred to as large tumor suppressor kinase, lats) [14]. The authors found that depletion of the wts gene resulted in increased cell proliferation, as well as abnormal morphogenesis. Four years later, two different laboratories identified two human homolog of the wts gene, large tumor suppressor kinase 1 (LATS1) [15] and h-warts (Human warts) [16]. In the early 2000s, several laboratories reported the core components of the Hippo pathway in Drosophila first, and soon after in mammalian species [11]. In the mammalian Hippo pathway, core components consist of Mammalian STE20-like kinase 1/2 (MST1/2) and an adaptor protein, Salvador family WW domain, containing protein 1 (SAV1), which can phosphorylate activate LATS1/2. Apart from MST1/2, two groups of mitogen-activated protein kinase kinase kinase kinases (MAP4Ks), MAP4K1/2/3/5 and MAP4K4/6/7, are also reported to directly phosphorylate LATS1/2 at their hydrophobic motifs. Once LATS1/2 is activated, its transcriptional coactivators, yes-associated protein (YAP) and WW Domain Containing Transcription Factor (WWTR1) (also known as TAZ), are phosphorylated and retained in the cytoplasm. When YAP and TAZ are dephosphorylated, they translocate to the nucleus and induce gene expression through their interaction with TEA Domain Family Members (TEAD), and the SMAD family of signal transduction proteins [17]. The Hippo pathway is summarized in Fig. 1, and a complete description of core components of the Hippo pathway, upstream signaling regulating it, mechanisms of activation and their transcriptional coactivators can be found in an excellent review of Meng and colleagues [11].
    The Hippo pathway signaling link with aging
    Hippo pathway signaling dysregulated in aging It is well known that a typical hallmark of aging is a steady increase of senescent cells. Stimuli such as DNA damage, oncogene, oxidative stress, mitochondrial dysfunction and DNA methylases/histone deacetylases inhibitors are all able to induce cell senescence [57]. If the cell is unable to control/reverse this process, the results are a pro-inflammatory microenvironment and a reduction of regenerative capacities in age-related dysfunction and diseases [57]. However, in cancer, cell senescence is a tumor suppressive mechanism. YAP/TAZ has been reported to play a key role in suppression of oncogene-RAS-induced senescence in human primary cells such as WI38 human primary lung fibroblasts, IMR90 human fibroblasts and HPNE ductal pancreatic cells. In fact, activation of YAP is enough to increase nucleotide metabolism and diminish senescent phenotypes including proliferation, morphological alterations, lysosomal activity and expression of SASP genes. Moreover, RAS and MEK1 inhibit YAP/TAZ transcriptional activity during induction of senescence while reduction of YAP/TAZ activity is enough to promote senescence-associated phenotypes [58]. Induction of senescence in human nucleus pulposus chondrocytes leads to an increase of the Hippo pathway activation and YAP phosphorylation and decrease of CTGF expression. In correspondence with this data, depletion of YAP promotes senescence through stimulation of p53/p21, and lysosomal activity [59]. In human periodontal ligament stem cells, YAP stimulates cell proliferation (assessed using EdU incorporation) and inhibits apoptosis whereas depletion of YAP promotes senescence [60]. Similarly, other studies have explained the role of the transcriptional co-activators downstream of the Hippo pathway in regulating cell senescence. In ethanol-induced cellular senescence, upregulation of YAP decreases senescence markers (p16, p21, HMGA1 and DNA damage marker γ‐H2AX) in hepatocytes [61]. In human fibroblast cells, progressive loss of YAP promotes concomitant increase of senescence through both the p53 and p16 pathways in a TEAD-dependent manner; in context of cancer, the authors reported that in mesothelioma and liver cancer YAP downregulation was also able to stimulate senescence [62]. When YAP is predominantly localized in the cytoplasm of senescent cells, the transcriptional activity of its target gene, its ability to self-repair and proliferate significantly decrease, its resistance to cellular senescence will also decrease.