Structural Basis for Autoactivation of Human Mst2 Kinase and Its Regulation by RASSF5

Ni, L.; Li, Sheng; Yu, Jianzhong; Min, Ji-Young; Brautigam, Chad A.; Tomchick, Diana R.; Pan, Duojia; Luo, Xuelian

doi:10.1016/j.str.2013.07.008

Cited by 86 publications

(148 citation statements)

References 49 publications

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“…To characterize potential structural differences between active and inactive Mst2, we analyzed 15 N-labeled human wild-type Mst2 and kinase-inactive Mst2 D146N proteins with nuclear magnetic resonance (NMR) spectroscopy. We showed previously that the linker region of human Mst2 is flexible (Ni et al 2013). Strikingly, we observed a new cluster of peaks a ∼8.5-9.0 ppm in the spectrum of Mst2…”

Section: Mst2 Autophosphorylates Its Linker To Create Phospho-dockingsupporting

confidence: 50%

“…Lats1C ΔHM and Lats1C were further purified by a Mono S cation exchange column followed by a Superdex 200 gel filtration column (GE Healthcare). The expression and purification of Mst2 WT , Mst2 D146N , Mst2 ΔL , and Mst2 KD were described previously (Ni et al 2013). The pMst2-Mob1 complex was obtained by mixing 30 mg/mL Mob1 ΔN50 with the pMst2 MBM peptide (DEEEED GpTMKRNATSPQVQRPSFMDYFDKQ) at 1:2 molar ratio.…”

Section: Protein Expression and Purificationmentioning

confidence: 99%

“…Mst1/2 can be activated through autophosphorylation at their activation loop, and this autophosphorylation requires Mst1/2 homodimerization through their C-terminal SARAH (Sav/Rassf/Hpo) domain (Avruch et al 2012;Jin et al 2012;Ni et al 2013). Activated Mst1/2 then phosphorylate and activate Lats1/2 (Chan et al 2005).…”

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confidence: 99%

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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: Mst2 Autophosphorylates Its Linker To Create Phospho-dockingsupporting

confidence: 50%

Section: Protein Expression and Purificationmentioning

confidence: 99%

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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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“…Nevertheless, it is evident that RASSFs disrupt MST1/2 dimerization and prevent their autophosphorylation. However, interaction of RASSFs with already activated MST1/2 may prevent MST1/2 dephosphorylation and therefore sustain MST1/2 kinase activity (Guo et al 2011;Ni et al 2013).…”

Section: The Regulation Of Lats-activating Kinases Mst1/2 and Map4ksmentioning

confidence: 99%

Mechanisms of Hippo pathway regulation

2016

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The Hippo pathway was initially identified in Drosophila melanogaster screens for tissue growth two decades ago and has been a subject extensively studied in both Drosophila and mammals in the last several years. The core of the Hippo pathway consists of a kinase cascade, transcription coactivators, and DNA-binding partners. Recent studies have expanded the Hippo pathway as a complex signaling network with >30 components. This pathway is regulated by intrinsic cell machineries, such as cell–cell contact, cell polarity, and actin cytoskeleton, as well as a wide range of signals, including cellular energy status, mechanical cues, and hormonal signals that act through G-protein-coupled receptors. The major functions of the Hippo pathway have been defined to restrict tissue growth in adults and modulate cell proliferation, differentiation, and migration in developing organs. Furthermore, dysregulation of the Hippo pathway leads to aberrant cell growth and neoplasia. In this review, we focus on recent developments in our understanding of the molecular actions of the core Hippo kinase cascade and discuss key open questions in the regulation and function of the Hippo pathway.

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“…4A and 6A). It has been reported that RASSF5 enables the HIPPO pathway (via MST2/ STK3) to respond to and integrate diverse cellular signals by acting as a positive regulator of MST2/STK3 (35). A recent study revealed a role of YAP, the central effector of the HIPPO pathway during HSC activation (13); thus, we analyzed whether ERAS activates the HIPPO pathway, which may lead to phosphorylation and proteolytic degradation of YAP (supplemental Figs.…”

Section: ⌬N/s/smentioning

confidence: 99%

The Role of Embryonic Stem Cell-expressed RAS (ERAS) in the Maintenance of Quiescent Hepatic Stellate Cells

Nakhaei‐Rad¹,

Nakhaeizadeh²,

Götze³

et al. 2016

Journal of Biological Chemistry

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Hepatic stellate cells (HSCs) were recently identified as liverresident mesenchymal stem cells. HSCs are activated after liver injury and involved in pivotal processes, such as liver development, immunoregulation, regeneration, and also fibrogenesis. To date, several studies have reported candidate pathways that regulate the plasticity of HSCs during physiological and pathophysiological processes. Here we analyzed the expression changes and activity of the RAS family GTPases and thereby investigated the signaling networks of quiescent HSCs versus activated HSCs. For the first time, we report that embryonic stem cell-expressed RAS (ERAS) is specifically expressed in quiescent HSCs and down-regulated during HSC activation via promoter DNA methylation. Notably, in quiescent HSCs, the high level of ERAS protein correlates with the activation of AKT, STAT3, mTORC2, and HIPPO signaling pathways and inactivation of FOXO1 and YAP. Our data strongly indicate that in quiescent HSCs, ERAS targets AKT via two distinct pathways driven by PI3K␣/␦ and mTORC2, whereas in activated HSCs, RAS signaling shifts to RAF-MEK-ERK. Thus, in contrast to the reported role of ERAS in tumor cells associated with cell proliferation, our findings indicate that ERAS is important to maintain quiescence in HSCs.

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Structural Basis for Autoactivation of Human Mst2 Kinase and Its Regulation by RASSF5

Cited by 86 publications

References 49 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

Mechanisms of Hippo pathway regulation

The Role of Embryonic Stem Cell-expressed RAS (ERAS) in the Maintenance of Quiescent Hepatic Stellate Cells

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