Activation of the Yeast Hippo Pathway by Phosphorylation-Dependent Assembly of Signaling Complexes

Rock, Jeremy M.; Lim, Daniel; Stach, Lasse; Ogrodowicz, R.W.; Keck, Jamie M.; Jones, Michele H.; Wong, Catherine C. L.; Yates, John R.; Winey, Mark; Smerdon, Stephen J.; Yaffe, Michael B.; Amon, Angelika

doi:10.1126/science.1235822

Cited by 95 publications

(172 citation statements)

References 19 publications

(41 reference statements)

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“…We refer to this site of Mob1 as the pT-binding site. The major interactions at this site involve the pTM dipeptide motif of pMst2 and are highly similar to those observed in the crystal structure of Mob1 bound to an unnatural phosphopeptide ligand (Rock et al 2013).…”

Section: Structure Of Mob1 Bound To a Pmst2 Peptidesupporting

confidence: 50%

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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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Section: Structure Of Mob1 Bound To a Pmst2 Peptidesupporting

confidence: 50%

“…The HS motif is not present in the unnatural phosphopeptide ligand of Mob1 reported earlier (Rock et al 2013). The HS-Mob1 interactions revealed in our structure are thus missing in the structure of Mob1 bound to that pS peptide.…”

Section: Structure Of Mob1 Bound To a Pmst2 Peptidementioning

confidence: 65%

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

et al. 2015

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“…Now that many of the regulatory relationships between the SIN proteins have been established, further mathematical modelling of the SIN will be useful as an aid to better describe our observations (Csikász-Nagy et al, 2007) and to make predictions that can be tested at the bench (Bajpai et al, 2013). Studies on the counterparts of the SIN in other organisms will also provide new hypotheses to test in S. pombe; for example, is the assembly of SIN proteins at the SPB also a phosphorylation-dependent event, as in the mitotic exit network of the budding yeast (Rock et al, 2013)? Conversely, insights into how the SIN is regulated and identification of its targets might help us to understand the MEN and HIPPO pathways.…”

Section: Future Directionsmentioning

confidence: 99%

Pombe's thirteen – control of fission yeast cell division by the septation initiation network

Simanis

2015

Journal of Cell Science

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The septation initiation network (SIN) regulates aspects of cell growth and division in Schizosaccharomyces pombe and is essential for cytokinesis. Insufficient signalling results in improper assembly of the contractile ring and failure of cytokinesis, generating multinucleated cells, whereas too much SIN signalling uncouples cytokinesis from the rest of the cell cycle. SIN signalling is therefore tightly controlled to coordinate cytokinesis with chromosome segregation. Signalling originates from the cytoplasmic face of the spindle pole body (SPB), and asymmetric localisation of some SIN proteins to one of the two SPBs during mitosis is important for regulation of the SIN. Recent studies have identified in vivo substrates of the SIN, which include components involved in mitotic control, those of the contractile ring and elements of the signalling pathway regulating polarised growth. The SIN is also required for spore formation following meiosis. This has provided insights into how the SIN performs its diverse functions in the cell cycle and shed new light on its regulation.

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“…Specifically, Nud1 is responsible for the SPB localization of the kinase Cdc15, and Cdc15 in turn is required for the recruitment and activation of the effector kinase complex Mob1 -Dbf2 [64]. Importantly, the SPB scaffolding proteins Nud1 and Cdc11 serve not only as assembly platforms for signalling components in budding and fission yeast, respectively, but they actively modulate downstream signalling events, depending on their phosphorylation status [65,66].…”

Section: (B) Exit From Mitosismentioning

confidence: 99%

Centrosomes as signalling centres

Arquint

Gabryjonczyk

Nigg

2014

Phil. Trans. R. Soc. B

125

109

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Centrosomes—as well as the related spindle pole bodies (SPBs) of yeast—have been extensively studied from the perspective of their microtubule-organizing roles. Moreover, the biogenesis and duplication of these organelles have been the subject of much attention, and the importance of centrosomes and the centriole–ciliary apparatus for human disease is well recognized. Much less developed is our understanding of another facet of centrosomes and SPBs, namely their possible role as signalling centres. Yet, many signalling components, including kinases and phosphatases, have been associated with centrosomes and spindle poles, giving rise to the hypothesis that these organelles might serve as hubs for the integration and coordination of signalling pathways. In this review, we discuss a number of selected studies that bear on this notion. We cover different processes (cell cycle control, development, DNA damage response) and organisms (yeast, invertebrates and vertebrates), but have made no attempt to be comprehensive. This field is still young and although the concept of centrosomes and SPBs as signalling centres is attractive, it remains primarily a concept—in need of further scrutiny. We hope that this review will stimulate thought and experimentation.

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Activation of the Yeast Hippo Pathway by Phosphorylation-Dependent Assembly of Signaling Complexes

Cited by 95 publications

References 19 publications

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

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

Pombe's thirteen – control of fission yeast cell division by the septation initiation network

Centrosomes as signalling centres

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