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

Ni, L.; Zheng, Yonggang; Hara, Mayuko; Pan, Duojia; Luo, Xuelian

doi:10.1101/gad.264929.115

Cited by 148 publications

(276 citation statements)

References 55 publications

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“…We have previously shown that upon phosphorylation at its activation loop in the kinase domain, Hpo/MST undergoes multisite autophosphorylation in an unstructured linker region between the kinase domain and the SARAH domain (Ni et al, 2015). Some of these sites serve as phospho-dependent docking sites that function together with a hydrophobic motif (HFM) (Figure 1A) to recruit Mats/MOB1 thus promoting Wts/LATS phosphorylation (Ni et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

“…Some of these sites serve as phospho-dependent docking sites that function together with a hydrophobic motif (HFM) (Figure 1A) to recruit Mats/MOB1 thus promoting Wts/LATS phosphorylation (Ni et al, 2015). While investigating the functional contribution of the remaining phosphorylation sites in the linker region, we found that, contrary to the Mats/MOB1 docking sites, these autophosphorylation sites play an opposite role in Hippo signaling.…”

Section: Introductionmentioning

confidence: 99%

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Homeostatic Control of Hpo/MST Kinase Activity through Autophosphorylation-Dependent Recruitment of the STRIPAK PP2A Phosphatase Complex

et al. 2017

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The Hippo pathway controls organ size and tissue homeostasis through a kinase cascade leading from the Ste20-like kinase Hpo (MST1/2 in mammals) to the transcriptional coactivator Yki (YAP/TAZ in mammals). While previous studies have uncovered positive and negative regulators of Hpo/MST, how they are integrated to maintain signaling homeostasis remains poorly understood. Here we identify a self-restricting mechanism whereby autophosphorylation of an unstructured linker in Hpo/MST creates docking sites for the STRIPAK PP2A phosphatase complex to inactivate Hpo/MST. Mutation of the phospho-dependent docking sites in Hpo/MST or deletion of Slmap, the STRIPAK subunit recognizing these docking sites, results in constitutive activation of Hpo/MST in both Drosophila and mammalian cells. In contrast, autophosphorylation of the Hpo/MST linker at distinct sites are known to recruit Mats/MOB1 to facilitate Hippo signaling. Thus, multisite autophosphorylation of Hpo/MST linker provides an evolutionarily conserved built-in molecular platform to maintain signaling homeostasis by coupling antagonistic signaling activities.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Homeostatic Control of Hpo/MST Kinase Activity through Autophosphorylation-Dependent Recruitment of the STRIPAK PP2A Phosphatase Complex

et al. 2017

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“…3; Ni et al 2015). MST2 autophosphorylates its long linker between the kinase domain and the SARA domain to generate a phosphor-docking motif, which can recruit MOB1.…”

Section: Mechanisms Of Hippo Kinase Cascade Activationmentioning

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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“…MST1/2 or MAP4Ks activate LATS1/2 by phosphorylating the hydrophobic motif residues in LATS1/2 [8][9][10][11][12][13][14]. Activated LATS1/2 then phosphorylate YAP and TAZ, leading to 14-3-3 binding and cytoplasmic retention [15].…”

Section: Introductionmentioning

confidence: 99%

Osmotic stress‐induced phosphorylation by NLK at Ser128 activates YAP

et al. 2016

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YAP is the major downstream effector of the Hippo pathway, which controls cell growth, tissue homeostasis, and organ size. Aberrant YAP activation, resulting from dysregulation of the Hippo pathway, is frequently observed in human cancers. YAP is a transcription co-activator, and the key mechanism of YAP regulation is its nuclear and cytoplasmic translocation. The Hippo pathway component, LATS, inhibits YAP by phosphorylating YAP at Ser127, leading to 14-3-3 binding and cytoplasmic retention of YAP. Here, we report that osmotic stress stimulates transient YAP nuclear localization and increases YAP activity even when YAP Ser127 is phosphorylated. Osmotic stress acts via the NLK kinase to induce YAP Ser128 phosphorylation. Phosphorylation of YAP at Ser128 interferes with its ability to bind to 14-3-3, resulting in YAP nuclear accumulation and induction of downstream target gene expression. This osmotic stress-induced YAP activation enhances cellular stress adaptation. Our findings reveal a critical role for NLK-mediated Ser128 phosphorylation in YAP regulation and a crosstalk between osmotic stress and the Hippo pathway.

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

Cited by 148 publications

References 55 publications

Homeostatic Control of Hpo/MST Kinase Activity through Autophosphorylation-Dependent Recruitment of the STRIPAK PP2A Phosphatase Complex

Homeostatic Control of Hpo/MST Kinase Activity through Autophosphorylation-Dependent Recruitment of the STRIPAK PP2A Phosphatase Complex

Mechanisms of Hippo pathway regulation

Osmotic stress‐induced phosphorylation by NLK at Ser128 activates YAP

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