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    • In mammalian cells Motins have been identified as a

    2022-08-08

    In mammalian cells, Motins have been identified as a key link between F-actin and Hippo pathway regulation, as knockdown of all three Motins increased Yap activity even in the presence of cytoskeletal disruption [105]. Motins can physically associate with F-actin but this association is blocked by phosphorylation of Motins by Lats kinases 83, 84, 105. Moreover, F-actin competes with YAP for binding to Motins. Thus, when LATS phosphorylates Amot-p130 to inhibit its binding to F-actin, it increases Amot-p130 binding to YAP and hence inhibition of YAP [105]. Notably, the influence of F-actin on Motin–YAP binding, together with potential sequestration of YAP through direct binding to Motins, also provides a possible explanation for observations of LATS-independent regulation of YAP by the cytoskeleton. Downregulation of YAP induced by disruption of the cyclohexamide cytoskeleton also requires protein kinase A in mammalian cells, which can directly phosphorylate LATS and enhance LATS activity [106]. In cultured Drosophila cells, cytoskeletal disruption increased Merlin–Wts binding, suggesting that F-actin accumulation could potentially modulate Hippo signaling by influencing interaction between Merlin and Wts [19]. Regulation of Wts activity by F-actin in Drosophila was also partially dependent on JNK activity [99]. JNK also contributes to the influence of cyclic stretch on YAP activity in mammalian cells [107], which occurs over a timescale that correlates with the reorganization of F-actin. JNK has a complex relationship to Hippo signaling, as in Drosophila, depending on the context, it can activate or inhibit Yki 108, 109, 110. A mechanism by which Yki is activated by JNK involves phosphorylation of Jub or one of its mammalian homologs, LIMD1; this phosphorylation promotes its ability to bind to, and hence inhibit, LATS [111].
    Regulation of Hippo Signaling by Cytoskeletal Tension In addition to mechanisms that appear to depend on accumulation of F-actin, mechanisms that could provide a basis for influences of tension within the actin cytoskeleton on Hippo signaling have been identified (Figure 4). As noted above, one such mechanism is the influence of cytoskeletal tension on integrin-dependent signaling. The actin cytoskeleton also forms attachments to the nuclear envelope. Intriguingly, a recent study reported that Nesprin 1 Giant, a protein required for attachment of the actin cytoskeleton to the nuclear membrane, is required for the activation of YAP in response to dynamic stretch in mesenchymal stem cells [112]. How this attachment is able to influence YAP activity remains to be determined. Epithelial cells are also mechanically coupled to each other at adherens junctions, which are attached to the actin cytoskeleton. In growing Drosophila epithelia, these cell–cell junctions are under tension, and this tension promotes Yki activity [20]. Activation of YAP that is promoted by stretching cells, and dependent on adherens junctions, has also been observed in cultured mammalian cells [113]. A mechanism for how tension at adherens junctions promotes Yki activity has been identified in Drosophila where the localization of Jub to adherens junctions is regulated by myosin activity [20]. This recruitment is mediated through α-catenin, which can act as a mechanotransducer: studies of the association between α-catenin and Vinculin have indicated that α-catenin, which links adherens junctions to the actin cytoskeleton, can undergo a tension-dependent conformational change that exposes, under high tension, a Vinculin-binding site [114]. This same conformational change might also influence binding between Jub and α-catenin. The Jub recruited to adherens junctions then recruits Wts to adherens junctions, which, leads to increased Yki activity because Jub is a Wts inhibitor. Conversely, when tension is lowered by reducing myosin activity, Jub and Wts recruitment to junctions is decreased, as is Yki activity [20]. The Spectrin cytoskeleton also appears to provide a link between tension and Hippo signaling, but the nature of this link remains unclear. Spectrins were found to influence Hippo signaling, both in Drosophila and in cultured mammalian cells, in three independent studies 115, 116, 117. Two of these suggested that Spectrins might be regulated by cytoskeletal tension and help transduce the effects of tension onto Hippo signaling, possibly through upstream regulators of Hippo signaling including Crumbs, Merlin, and Kibra 115, 116. The other study, by contrast, reported that Spectrins influence myosin phosphorylation and suggested that Spectrins might influence Hippo signaling by affecting actomyosin contractility [117]. Thus, while Spectrins clearly have an influence on Hippo signaling, defining the mechanism by which they regulate the Hippo network requires further study.