Regulation of localization and function of the transcriptional co-activator YAP by angiomotin

Moleirinho, Susana; Hoxha, Sany; Mandati, Vinay; Curtale, Graziella; Troutman, Scott; Ehmer, Ursula; Kissil, Joseph L.

doi:10.7554/elife.23966

Cited by 77 publications

(81 citation statements)

References 60 publications

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“…Arid1A-SWI/SNF do not affect YAP/TAZ nuclear localization; thus, this pathway acts in conjunction with angiomotins, the Hippo pathway, and other factors that influence YAP/TAZ nuclear localization. Angiomotins have also been reported in the nucleus (80), and it will be interesting in future studies to determine whether they can regulate YAP/TAZ in the nucleus in response to changes in nuclear F-actin.…”

Section: Nuclear Actin Sensingmentioning

confidence: 99%

Control of cellular responses to mechanical cues through YAP/TAZ regulation

Dasgupta

McCollum

2019

Journal of Biological Chemistry

247

190

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To perceive their three-dimensional environment, cells and tissues must be able to sense and interpret various physical forces like shear, tensile, and compression stress. These forces can be generated both internally and externally in response to physical properties, like substrate stiffness, cell contractility, and forces generated by adjacent cells. Mechanical cues have important roles in cell fate decisions regarding proliferation, survival, and differentiation as well as the processes of tissue regeneration and wound repair. Aberrant remodeling of the extracellular space and/or defects in properly responding to mechanical cues likely contributes to various disease states, such as fibrosis, muscle diseases, and cancer. Mechanotransduction involves the sensing and translation of mechanical forces into biochemical signals, like activation of specific genes and signaling cascades that enable cells to adapt to their physical environment. The signaling pathways involved in mechanical signaling are highly complex, but numerous studies have highlighted a central role for the Hippo pathway and other signaling networks in regulating the YAP and TAZ (YAP/TAZ) proteins to mediate the effects of mechanical stimuli on cellular behavior. How mechanical cues control YAP/TAZ has been poorly understood. However, rapid progress in the last few years is beginning to reveal a surprisingly diverse set of pathways for controlling YAP/TAZ. In this review, we will focus on how mechanical perturbations are sensed through changes in the actin cytoskeleton and mechanosensors at focal adhesions, adherens junctions, and the nuclear envelope to regulate YAP/TAZ.

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Section: Nuclear Actin Sensingmentioning

confidence: 99%

Control of cellular responses to mechanical cues through YAP/TAZ regulation

Dasgupta

McCollum

2019

Journal of Biological Chemistry

247

190

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“…Intriguingly, the Hippo signaling pathway is regulated by a series of PPxY/WW-domain modular interactions which lead ultimately to either sequestration or degradation of phosphorylated YAP in the cytoplasm (Hippo on), or to localization of unphosphorylated YAP in the nucleus where it upregulates a series of TEAD genes involved in cell growth and proliferation (Hippo off) [58]. One of the key regulators of YAP/TAZ localization and Hippo pathway activity is angiomotin (Amot), a member of the angiomotin family (Amot, AmotL1, and AmotL2), all of which contain multiple PPxY motifs at their N-termini [59][60][61][62][63][64][65]. Indeed, the PPxY/WW-domain interaction between Amot and YAP is well-characterized and reported to affect multiple processes in the cell [60][61][62][64][65][66][67][68][69].…”

Section: -271) and Imcb (M-r02010mentioning

confidence: 99%

Modular mimicry and engagement of the Hippo pathway by Marburg virus VP40: Implications for filovirus biology and budding

et al. 2020

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Ebola (EBOV) and Marburg (MARV) are members of the Filoviridae family, which continue to emerge and cause sporadic outbreaks of hemorrhagic fever with high mortality rates. Filoviruses utilize their VP40 matrix protein to drive virion assembly and budding, in part, by recruitment of specific WW-domain-bearing host proteins via its conserved PPxY Late (L) domain motif. Here, we screened an array of 115 mammalian, bacterially expressed and purified WW-domains using a PPxY-containing peptide from MARV VP40 (mVP40) to identify novel host interactors. Using this unbiased approach, we identified Yes Associated Protein (YAP) and Transcriptional co-Activator with PDZ-binding motif (TAZ) as novel mVP40 PPxY interactors. YAP and TAZ function as downstream transcriptional effectors of the Hippo signaling pathway that regulates cell proliferation, migration and apoptosis. We demonstrate that ectopic expression of YAP or TAZ along with mVP40 leads to significant inhibition of budding of mVP40 VLPs in a WW-domain/PPxY dependent manner. Moreover, YAP colocalized with mVP40 in the cytoplasm, and inhibition of mVP40 VLP budding was more pronounced when YAP was localized predominantly in the cytoplasm rather than in the nucleus. A key regulator of YAP nuclear/cytoplasmic localization and function is angiomotin (Amot); a multi-PPxY containing protein that strongly interacts with YAP WW-domains. Interestingly, we found that expression of PPxY-containing Amot rescued mVP40 VLP egress from either YAP-or TAZ-mediated inhibition in a PPxY-dependent manner. Importantly, using a stable Amot-knockdown cell line, we found that expression of Amot was critical for efficient egress of mVP40 VLPs as well as egress and spread of authentic MARV in infected cell cultures. In sum, we identified novel negative (YAP/TAZ) and positive (Amot) regulators of MARV VP40-mediated egress, that likely function in part, via competition between host and viral PPxY motifs binding to modular host WW-domains. These findings

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“…Angiomotins bind to both LATS1/2 and YAP and can inhibit YAP through two mechanisms: binding and retention of YAP in the cytoplasm/plasma membrane and activation of LATS1/2 (21, 24 -27). Other studies have shown that AMOT can control YAP nuclear/cytoplasmic localization, depending on its phosphorylation state (28). Angiomotins also bind the LATS1/2 activator NF2 (29,30), and a study using proximity labeling found that SAV1 and MOB1 may interact with AMOT (31).…”

mentioning

confidence: 98%

Angiomotins stimulate LATS kinase autophosphorylation and act as scaffolds that promote Hippo signaling

Mana‐Capelli

McCollum

2018

Journal of Biological Chemistry

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The Hippo pathway controls cell proliferation, differentiation, and survival by regulating the Yes-associated protein (YAP) transcriptional coactivator in response to various stimuli, including the mechanical environment. The major YAP regulators are the LATS1/2 kinases, which phosphorylate and inhibit YAP. LATS1/2 are activated by phosphorylation on a hydrophobic motif (HM) outside of the kinase domain by MST1/2 and other kinases. Phosphorylation of the HM motif then triggers autophosphorylation of the kinase in the activation loop to fully activate the kinase, a process facilitated by MOB1. The angiomotin family of proteins (AMOT, AMOTL1, and AMOTL2) bind LATS1/2 and promote its kinase activity and YAP phosphorylation through an unknown mechanism. Here we show that angiomotins increase Hippo signaling through multiple mechanisms. We found that, by binding LATS1/2, SAV1, and YAP, angiomotins function as a scaffold that connects LATS1/2 to both its activator SAV1-MST1 and its target YAP. Deletion of all three angiomotins reduced the association of LATS1 with SAV1-MST1 and decreased MST1/2-mediated LATS1/2-HM phosphorylation. Angiomotin deletion also reduced LATS1/2's ability to associate with and phosphorylate YAP. In addition, we found that angiomotins have an unexpected function along with MOB1 to promote autophosphorylation of LATS1/2 on the activation loop motif independent of HM phosphorylation. These results indicate that angiomotins enhance Hippo signaling by stimulating LATS1/2 autophosphorylation and by connecting LATS1/2 with both its activator SAV1-MST1/2 and its substrate YAP.

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Regulation of localization and function of the transcriptional co-activator YAP by angiomotin

Cited by 77 publications

References 60 publications

Control of cellular responses to mechanical cues through YAP/TAZ regulation

Control of cellular responses to mechanical cues through YAP/TAZ regulation

Modular mimicry and engagement of the Hippo pathway by Marburg virus VP40: Implications for filovirus biology and budding

Angiomotins stimulate LATS kinase autophosphorylation and act as scaffolds that promote Hippo signaling

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