Hippo Gains Weight: Added Insights and Complexity to Pathway Control

Enderle, Leonie; McNeill, Helen

doi:10.1126/scisignal.2004208

Cited by 65 publications

(76 citation statements)

References 115 publications

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“…The Hippo signaling pathway is an emerging growth control pathway that is conserved from Drosophila to mammals [1,2]. In Drosophila, the core kinase complex of Hippo pathway includes Ste20-like kinase Hippo (Hpo) and NDR family kinase Warts (Wts), as well as the adaptor proteins, including Salvador (Sav) and Mob as tumor suppressor (Mats) [3]. When Hpo is activated by upstream regulators, the active Hpo subsequently phosphorylates and activates Wts, which phosphorylates the transcriptional coactivator Yorkie (Yki), restricting its distribution in the cytoplasm by promoting its interaction with 14-3-3.…”

Section: Introductionmentioning

confidence: 99%

Brahma regulates the Hippo pathway activity through forming complex with Yki–Sd and regulating the transcription of Crumbs

Zhu

Liu

Wang

et al. 2015

Cellular Signalling

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The Hippo signaling pathway restricts organ size by inactivating the Yorkie (Yki)/Yes-associated protein (YAP) family proteins. The oncogenic Yki/YAP transcriptional coactivator family promotes tissue growth by activating target gene transcription, but the regulation of Yki/YAP activation remains elusive. In mammalian cells, we identified Brg1, a major subunit of chromatin-remodeling SWI/SNF family proteins, which interacts with YAP. This finding led us to investigate the in vivo functional interaction of Yki and Brahma (Brm), the Drosophila homolog of Brg1. We found that Brm functions at the downstream of Hippo pathway and interacts with Yki and Scalloped (Sd) to promotes Yki-dependent transcription and tissue growth. Furthermore, we demonstrated that Brm is required for the Crumbs (Crb) dysregulation-induced Yki activation. Interestingly, we also found that crb is a downstream target of Yki-Brm complex. Brm physically binds to the promoter of crb and regulates its transcription through Yki. Together, we showed that Brm functions as a critical regulator of Hippo signaling during tissue growth and plays an important role in the feedback loop between Crb and Yki.

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Section: Introductionmentioning

confidence: 99%

Brahma regulates the Hippo pathway activity through forming complex with Yki–Sd and regulating the transcription of Crumbs

Zhu

Liu

Wang

et al. 2015

Cellular Signalling

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“…Previous studies revealed a general role of G-protein-coupled receptors (GPCRs) as prime regulators of Hippo signaling, where LATS1/2 kinases are acutely inhibited by the extracellular hormones, such as lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) (Park and Guan 2013;Wackerhage et al 2014). In addition to hormonal regulation, several properties of tissue architecture, such as apical-basal polarity, planar cell polarity, and various types of cell-cell junctions, have been implicated in Hippo pathway regulation (Enderle and McNeill 2013;Thompson et al 2013). Moreover, studies have revealed that YAP/ TAZ are regulated by mechanical cues, such as extracellular matrix (ECM) stiffness and traction forces exerted by neighboring cells (Halder et al 2012;Low et al 2014).…”

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confidence: 99%

A YAP/TAZ-induced feedback mechanism regulates Hippo pathway homeostasis

et al. 2015

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YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif) are major downstream effectors of the Hippo pathway that influences tissue homeostasis, organ size, and cancer development. Aberrant hyperactivation of YAP/TAZ causes tissue overgrowth and tumorigenesis, whereas their inactivation impairs tissue development and regeneration. Dynamic and precise control of YAP/TAZ activity is thus important to ensure proper physiological regulation and homeostasis of the cells. Here, we show that YAP/TAZ activation results in activation of their negative regulators, LATS1/2 (large tumor suppressor 1/2) kinases, to constitute a negative feedback loop of the Hippo pathway in both cultured cells and mouse tissues. YAP/TAZ in complex with the transcription factor TEAD (TEA domain family member) directly induce LATS2 expression. Furthermore, YAP/TAZ also stimulate the kinase activity of LATS1/2 through inducing NF2 (neurofibromin 2). This feedback regulation is responsible for the transient activation of YAP upon lysophosphatidic acid (LPA) stimulation and the inhibition of YAP-induced cell migration. Thus, this LATS-mediated feedback loop provides an efficient mechanism to establish the robustness and homeostasis of YAP/TAZ regulation. Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ; also known as WWTR1) play pivotal roles in regulating cell proliferation, survival, and differentiation; organ development; regeneration; and stem cell biology (Barry and Camargo 2013;Johnson and Halder 2014;Mo et al. 2014;Piccolo et al. 2014). YAP and TAZ share ∼50% amino acid sequence identity with a similar domain organization, each containing a TEAD (TEA domain family member)-binding domain, a WW domain, and a C-terminal transactivation domain. YAP and TAZ are transcriptional coactivators that shuttle between the cytoplasm and the nucleus, where they associate with several transcription factorsmainly TEAD transcription factors (Zhao et al. 2008).

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“…Lats1/2-mediated phosphorylation inhibits YAP by promoting its cytoplasmic sequestration (Dong et al 2007;Zhao et al 2007;Hao et al 2008) and ubiquitination-dependent degradation (Zhao et al 2010b), thereby inhibiting the expression of Hippo-responsive genes, halting proliferation, and promoting apoptosis. Although recent genetic screens and biochemical studies have identified many upstream regulators of the Hippo pathway (Boggiano and Fehon 2012;Enderle and McNeill 2013), the activation mechanisms of the core Mst-Lats kinase cascade are still poorly understood.…”

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confidence: 99%

Structural basis for Mob1-dependent activation of the core Mst–Lats kinase cascade in Hippo signaling

et al. 2015

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The Mst-Lats kinase cascade is central to the Hippo tumor-suppressive pathway that controls organ size and tissue homeostasis. The adaptor protein Mob1 promotes Lats activation by Mst, but the mechanism remains unknown. Here, we show that human Mob1 binds to autophosphorylated docking motifs in active Mst2. This binding enables Mob1 phosphorylation by Mst2. Phosphorylated Mob1 undergoes conformational activation and binds to Lats1. We determine the crystal structures of phospho-Mst2-Mob1 and phospho-Mob1-Lats1 complexes, revealing the structural basis of both phosphorylation-dependent binding events. Further biochemical and functional analyses demonstrate that Mob1 mediates Lats1 activation through dynamic scaffolding and allosteric mechanisms. Thus, Mob1 acts as a phosphorylation-regulated coupler of kinase activation by virtue of its ability to engage multiple ligands. We propose that stepwise, phosphorylation-triggered docking interactions of nonkinase elements enhance the specificity and robustness of kinase signaling cascades.

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Hippo Gains Weight: Added Insights and Complexity to Pathway Control

Cited by 65 publications

References 115 publications

Brahma regulates the Hippo pathway activity through forming complex with Yki–Sd and regulating the transcription of Crumbs

Brahma regulates the Hippo pathway activity through forming complex with Yki–Sd and regulating the transcription of Crumbs

A YAP/TAZ-induced feedback mechanism regulates Hippo pathway homeostasis

Structural basis for Mob1-dependent activation of the core Mst–Lats kinase cascade in Hippo signaling

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