Salt-inducible kinases regulate growth through the Hippo signalling pathway in Drosophila

1] Apoptosis and Proliferation Control Laboratory, Cancer Research UK, London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK [2] Research Group Gene Expression, Max Planck Institute of Experimental Medicine, Hermann-Rein-Straße 3, D-37075 Göttingen, Germany.
Nature Cell Biology (Impact Factor: 19.68). 12/2012; 15(1). DOI: 10.1038/ncb2658
Source: PubMed


The specification of tissue size during development involves the coordinated action of many signalling pathways responding to organ-intrinsic signals, such as morphogen gradients, and systemic cues, such as nutrient status. The conserved Hippo (Hpo) pathway, which promotes both cell-cycle exit and apoptosis, is a major determinant of size control. The pathway core is a kinase cassette, comprising the kinases Hpo and Warts (Wts) and the scaffold proteins Salvador (Sav) and Mats, which inactivates the pro-growth transcriptional co-activator Yorkie (Yki). We performed a split-TEV-based genome-wide RNAi screen for modulators of Hpo signalling. We characterize the Drosophila salt-inducible kinases (Sik2 and Sik3) as negative regulators of Hpo signalling. Activated Sik kinases increase Yki target expression and promote tissue overgrowth through phosphorylation of Sav at Ser 413. As Sik kinases have been implicated in nutrient sensing, this suggests a link between the Hpo pathway and systemic growth control.

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    • "As another alternative to the reactivation of Hippo signalling approach, one could consider stimulators of YAP/TAZ activities as drug targets. Homeodomain interacting protein kinases (HIPKs) [109] and salt-inducible kinases (SIKs) [110] represent possible drug targets to blunt YAP (and possibly also TAZ) activity, as both kinases promote YAP activity in human cells. However, the molecular mechanism(s) of how these kinases promote YAP activity in human cells are to be understood in detail before rational drug design approaches can be initiated. "
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    ABSTRACT: The Hippo tumour suppressor pathway co-ordinates cell proliferation, cell death and cell differentiation to regulate tissue growth control. In mammals, a conserved core Hippo signalling module receives signal inputs on different levels to ensure the proper regulation of YAP/TAZ activities as transcriptional co-activators. While the core module members MST1/2, Salvador, LATS1/2 and MOB1 have been attributed tumour suppressive functions, YAP/TAZ have been mainly described to have oncogenic roles, although some reports provided evidence supporting growth suppressive roles of YAP/TAZ in certain cancer settings. Intriguingly, mammalian Hippo signalling is also implicated in non-cancer diseases and plays a role in tissue regeneration following injury. Cumulatively, these findings indicate that the pharmacological inhibition or activation of the Hippo pathway could be desirable depending on the disease context. In this review, we first summarise the functions of the mammalian Hippo pathway in tumour formation, and then discuss non-cancer diseases involving Hippo signalling core components with a specific focus on our current understanding of the non-cancer roles of MST1/2 and YAP/TAZ. In addition, the pros and cons of possible pharmacological interventions with Hippo signalling will be reviewed, with particular emphasis on anti-cancer drug development and regenerative medicine.
    Clinical and Translational Medicine 07/2014; 3(1):22. DOI:10.1186/2001-1326-3-22
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    • "Components of this core cassette can be regulated by distinct upstream factors to define the eventual biological outputs. For example, GPCR signaling regulates Wts directly [46], Sik kinases regulate Sav [47], and a set of FERM-domain proteins including Merlin (Mer) and Expanded (Ex) act upstream to activate Hpo by an as yet undefined mechanism [48]. "
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    ABSTRACT: Alcohol-mediated cancers represent more than 3.5% of cancer-related deaths, yet how alcohol promotes cancer is a major open question. Using Drosophila, we identified novel interactions between dietary ethanol and loss of tumor suppressor components of the Hippo Pathway. The Hippo Pathway suppresses tumors in flies and mammals by inactivating transcriptional co-activator Yorkie, and the spectrum of cancers associated with impaired Hippo signaling overlaps strikingly with those associated with alcohol. Therefore, our findings may implicate loss of Hippo Pathway tumor suppression in alcohol-mediated cancers. Ethanol enhanced overgrowth from loss of the expanded, hippo, or warts tumor suppressors but, surprisingly, not from over-expressing the yorkie oncogene. We propose that in parallel to Yorkie-dependent overgrowth, impairing Hippo signaling in the presence of alcohol may promote overgrowth via additional alcohol-relevant targets. We also identified interactions between alcohol and Hippo Pathway over-activation. We propose that exceeding certain thresholds of alcohol exposure activates Hippo signaling to maintain proper growth control and prevent alcohol-mediated mis-patterning and tissue overgrowth.
    PLoS ONE 10/2013; 8(10):e78880. DOI:10.1371/journal.pone.0078880 · 3.23 Impact Factor
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    • "Both regulatory mechanisms appear to be conserved from flies to humans, since human TAO1 can also activate MST2 [31], and HIPK2 promotes YAP activity in human cells [33]. In addition, Sik (salt-inducible kinase) has recently been shown to be required for Hippo signalling by phosphorylating Salvador in flies [34]. However, while human SIK2 can also inhibit YAP activity in HEK293 cells, the molecular mechanism must be different between flies and mammals, since the phosphorylation site in Drosophila Salvador is not conserved in mammals [34]. "
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    ABSTRACT: The metazoan Hippo pathway is an essential tumour suppressor signalling cascade that ensures normal tissue growth by co-ordinating cell proliferation, cell death and cell differentiation. Over the past years, various genetic and biochemical studies in Drosophila and mammals have defined a conserved core Hippo signalling module, composed of members of the Ste20-like kinase, the MOB co-activator and the AGC kinase families. In Drosophila, stimulated Hippo kinase phosphorylates and thereby activates the Mats/Warts complex, which consequently phosphorylates and inactivates the transcriptional co-activator Yorkie. In mammals, the counterparts of the Hippo/Mats/Warts/Yorkie cascade, namely MST1/2, MOB1A/B, LATS1/2 and YAP/TAZ, function in a similar fashion. These canonical Hippo pathways are so highly conserved that human MST2, hMOB1A and LATS1 can compensate for the loss of Hippo, Mats and Warts in flies. However, recent reports have shown that Hippo signalling is more diverse and complex, in particular in mammals. In this review, we summarize our current understanding of mammalian LATS1/2 kinases together with their closest relatives, the NDR1/2 kinases. The regulation of the LATS/NDR family of kinases will be discussed, followed by a summary of all currently known LATS/NDR substrates. Last, but not least, the biological roles of LATS/NDR kinases will be reviewed with specific emphasis on recent discoveries of canonical and non-canonical LATS/NDR functions in the extended Hippo pathway.
    Cell and Bioscience 08/2013; 3(1):32. DOI:10.1186/2045-3701-3-32 · 3.63 Impact Factor
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