Cellular Organization and Cytoskeletal Regulation of the Hippo Signaling Network

Sun, Shyan; Irvine, Kenneth D.

doi:10.1016/j.tcb.2016.05.003

Cited by 122 publications

(133 citation statements)

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“…45,46 A more complete understanding should involve these segments, as well as a mechanistic structural grasp of how MST activates the Hippo pathway and exactly how the Hippo pathway and YAP1 can rescue Ras and MAPK inhibition. Mutations in YAP1 are frequently observed in Ras-driven cancers, 10,11,14,47,48 and more. 15,16 RASSF5 tumor suppressor is currently among the key drug targets in Ras-related cancers due to its role in linking Ras/MAPK and YAP1.…”

Section: Resultsmentioning

confidence: 99%

“…3–9 Hippo’s signaling stimulates phosphorylation and thereby activation of a core kinase cascade including MST1/2 and large tumor suppressor 1/2 (LATS1/2), leading to phosphorylation of Yes associated protein 1 (YAP1). 10,11 YAP1’s phosphorylation encodes its degradation, thus abolishing its transcriptional activity. 12 Overexpression amplifies oncogenic signaling through YAP1’s association with the TEA domain (TEAD) family of transcription factors.…”

Section: Introductionmentioning

confidence: 99%

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The dynamic mechanism of RASSF5 and MST kinase activation by Ras

Liao

Jang

Tsai

et al. 2017

Phys. Chem. Chem. Phys.

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As a tumor suppressor, RASSF5 (NORE1A) activates MST1/2 thereby modulating the Hippo pathway. Structurally, activation involves RASSF5 and MST1/2 swapping their SARAH domains to form a SARAH heterodimer. This exposes the MST1/2 kinase domain which homodimerizes, leading to trans-autophosphorylation. The SARAH-SARAH interaction shifts RASSF5 away from its autoinhibited state and relieves MST1/2 autoinhibition. Separate crystal structures are available for the RA (Ras association) domain and SARAH dimer, where SARAH is a long straight α-helix. Using all-atom molecular dynamics simulations, we modeled the RASSF5 RA with a covalently connected SARAH to elucidate the dynamic mechanism of how SARAH mediates between autoinhibition and Ras triggered-activation. Our results show that in inactive RASSF5 the RA domain retains SARAH, yielding a self-associated conformation in which SARAH is in a kinked α-helical motif that increases the binding interface. When RASSF5 binds K-Ras4B-GTP, the equilibrium shifts toward SARAH’s interacting with MST. Since the RA/SARAH affinity is relatively low, whereas that of the SARAH heterodimer is in the nM range, we suggest that RASSF5 exerts its tumor suppressor action through competition with other Ras effectors for Ras effector binding site, as well as coincidentally its recruitment to the membrane to help MST activation. Thus, SARAH plays a key role in RASSF5’s tumor suppression action by linking the two major pathways in tumor cell proliferation: Ras and the MAPK (tumor cell proliferation-promoting) pathway, and the Hippo (tumor cell proliferation-suppressing) pathway.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The dynamic mechanism of RASSF5 and MST kinase activation by Ras

Liao

Jang

Tsai

et al. 2017

Phys. Chem. Chem. Phys.

View full text Add to dashboard Cite

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“…To exert this regulation, the pathway integrates several upstream inputs, such as scaffolding proteins forming activation complexes in close proximity to cell junctions (rendering Hippo sensitive to cell-cell contacts and cell polarity); signals from extracellular matrix and cytoskeleton and mechanical tension (reviewed in Yu & Guan 2013, Johnson & Halder 2014, Sun & Irvine 2016. The core of the mammalian Hippo signaling network comprises the kinases mammalian STE20-like protein kinase 1 (MST1), MST2, large tumor suppressor homolog 1 (LATS1) and LATS2 (Fig.…”

Section: Hippo Pathway: a New Player In Pituitary Stem Cell Regulation?mentioning

confidence: 99%

Pituitary stem cell regulation: who is pulling the strings?

Cox

Roose

Vennekens

et al. 2017

Journal of Endocrinology

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The pituitary gland plays a pivotal role in the endocrine system, steering fundamental processes of growth, metabolism, reproduction and coping with stress. The adult pituitary contains resident stem cells, which are highly quiescent in homeostatic conditions. However, the cells show marked signs of activation during processes of increased cell remodeling in the gland, including maturation at neonatal age, adaptation to physiological demands, regeneration upon injury and growth of local tumors. Although functions of pituitary stem cells are slowly but gradually uncovered, their regulation largely remains virgin territory. Since postnatal stem cells in general reiterate embryonic developmental pathways, attention is first being given to regulatory networks involved in pituitary embryogenesis. Here, we give an overview of the current knowledge on the NOTCH, WNT, epithelial-mesenchymal transition, SHH and Hippo pathways in the pituitary stem/progenitor cell compartment during various (activation) conditions from embryonic over neonatal to adult age. Most information comes from expression analyses of molecular components belonging to these networks, whereas functional extrapolation is still very limited. From this overview, it emerges that the 'big five' embryonic pathways are indeed reiterated in the stem cells of the 'lazy' homeostatic postnatal pituitary, further magnified en route to activation in more energetic, physiological and pathological remodeling conditions. Increasing the knowledge on the molecular players that pull the regulatory strings of the pituitary stem cells will not only provide further fundamental insight in postnatal pituitary homeostasis and activation, but also clues toward the development of regenerative ideas for improving treatment of pituitary deficiency and tumors.

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“…The only manipulation described that causes an increase in neuromast size is the upregulation of Wnt signaling, while the size of the primordium increases after inhibition of the Hippo pathway member amotl2a (Agarwala et al, 2015; Head et al, 2013; Wada et al, 2013; Wada and Kawakami, 2015; Jacques et al, 2014). The Hippo pathway controls organ size via a kinase cascade that leads to the phosphorylation and degradation of the transcriptional co-activators Yap/Taz (Sun and Irvine, 2016). In the absence of pathway activation, Yap/Taz are translocated to the nucleus where they activate proliferation and survival genes.…”

Section: Introductionmentioning

confidence: 99%

Proliferation-independent regulation of organ size by Fgf/Notch signaling

Kozlovskaja-Gumbrienė

Ren

Richard

et al. 2017

eLife

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Organ morphogenesis depends on the precise orchestration of cell migration, cell shape changes and cell adhesion. We demonstrate that Notch signaling is an integral part of the Wnt and Fgf signaling feedback loop coordinating cell migration and the self-organization of rosette-shaped sensory organs in the zebrafish lateral line system. We show that Notch signaling acts downstream of Fgf signaling to not only inhibit hair cell differentiation but also to induce and maintain stable epithelial rosettes. Ectopic Notch expression causes a significant increase in organ size independently of proliferation and the Hippo pathway. Transplantation and RNASeq analyses revealed that Notch signaling induces apical junctional complex genes that regulate cell adhesion and apical constriction. Our analysis also demonstrates that in the absence of patterning cues normally provided by a Wnt/Fgf signaling system, rosettes still self-organize in the presence of Notch signaling.DOI: http://dx.doi.org/10.7554/eLife.21049.001

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Cellular Organization and Cytoskeletal Regulation of the Hippo Signaling Network

Cited by 122 publications

References 118 publications

The dynamic mechanism of RASSF5 and MST kinase activation by Ras

The dynamic mechanism of RASSF5 and MST kinase activation by Ras

Pituitary stem cell regulation: who is pulling the strings?

Proliferation-independent regulation of organ size by Fgf/Notch signaling

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