Angiomotins link F-actin architecture to Hippo pathway signaling

Mana‐Capelli, Sebastian; Paramasivam, M.; Dutta, Shubham; McCollum, Dannel

doi:10.1091/mbc.e13-11-0701

Cited by 167 publications

(193 citation statements)

References 27 publications

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“…A high level of F-actin could sequester angiomotins, leaving YAP and Ser(P) 112 -YAP free to be imported into the nucleus. In support to this notion, it was also reported that knocking down angiomotins significantly rescued YAP nuclear localization in blebbistatin-treated cells (24). In support of our findings of an F-actin-dependent pathway of YAP nuclear localization, it was shown that knocking down the actin depolymerization factor cofilin, which is known to increase the F:G-actin ratio (28), rescued YAP transcriptional activity on soft substrates (10).…”

Section: Ser(p)supporting

confidence: 89%

“…Our data provides a step forward in understanding actinmediated YAP nuclear localization beyond the requirement of actomyosin contractility and Ser 112 phosphorylation of YAP. A possible molecular player for such actin-mediated YAP regulation is through angiomotin-like proteins (24). Angiomotins bind the WW domain of YAP independent of its phosphorylation at Ser 112 residue, and overexpression of angiomotin could sequester constitutively active YAP (YAP S112A ) in the cytoplasm (45).…”

Section: Discussionmentioning

confidence: 99%

“…Angiomotins bind the WW domain of YAP independent of its phosphorylation at Ser 112 residue, and overexpression of angiomotin could sequester constitutively active YAP (YAP S112A ) in the cytoplasm (45). Angiomotins competitively bind to both F-actin and YAP, and overexpression of an actin binding mutant of angiomotin sequesters more YAP in the cytoplasm than overexpression of wild-type protein (24). This mechanism could underlie our observations that a high F:G-actin ratio in control and myosin-inhibited cells was associated with both YAP and FIGURE 5.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, LATS1/ 2-independent regulation of YAP can be achieved in cells cultured on soft, small matrices or at high cell density by promotion of actin assembly via depletion of the actin depolymerizing factor Cofilin, or the filament capping proteins capZ or gelsolin (10). Further complicating these findings, it has also been shown that myosin inhibition by blebbistatin only partially affects YAP nuclear localization, yet it was predominantly dependent on the actin-binding protein angiomotin (24).…”

mentioning

confidence: 99%

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YAP Nuclear Localization in the Absence of Cell-Cell Contact Is Mediated by a Filamentous Actin-dependent, Myosin II- and Phospho-YAP-independent Pathway during Extracellular Matrix Mechanosensing

Das

Fischer

Pan

et al. 2016

Journal of Biological Chemistry

193

143

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Cell-cell contact inhibition and the mechanical environment of cells have both been shown to regulate YAP nuclear localization to modulate cell proliferation. Changes in cellular contractility by genetic, pharmacological, and matrix stiffness perturbations regulate YAP nuclear localization. However, because contractility and F-actin organization are interconnected cytoskeletal properties, it remains unclear which of these distinctly regulates YAP localization. Here we show that in the absence of cell-cell contact, actomyosin contractility suppresses YAP phosphorylation at Ser 112 , however, neither loss of contractility nor increase in YAP phosphorylation is sufficient for its nuclear exclusion. We find that actin cytoskeletal integrity is essential for YAP nuclear localization, and can override phosphoregulation or contractility-mediated regulation of YAP nuclear localization. This actin-mediated regulation is conserved during mechanotransduction, as substrate compliance increased YAP phosphorylation and reduced cytoskeletal integrity leading to nuclear exclusion of both YAP and Ser(P) 112 -YAP. These data provide evidence for two actin-mediated pathways for YAP regulation; one in which actomyosin contractility regulates YAP phosphorylation, and a second that involves cytoskeletal integrity-mediated regulation of YAP nuclear localization independent of contractility. We suggest that in non-contact inhibited cells, this latter mechanism may be important in low stiffness regimes, such as may be encountered in physiological environments.

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Section: Ser(p)supporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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YAP Nuclear Localization in the Absence of Cell-Cell Contact Is Mediated by a Filamentous Actin-dependent, Myosin II- and Phospho-YAP-independent Pathway during Extracellular Matrix Mechanosensing

Das

Fischer

Pan

et al. 2016

Journal of Biological Chemistry

193

143

View full text Add to dashboard Cite

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“…Although it seems likely that changes in gene expression also result from such Mpk1 activation, this possibility does not appear to have been examined. In mammalian cells, both actin and actin-binding proteins participate in transcriptional and post-transcriptional regulation of a variety of genes in response to shocks to the actin cytoskeleton (Miralles and Visa 2006;Olson and Nordheim 2010;Aragona et al 2013;Mana-Capelli et al 2014). In the best-studied case, perturbations in F-actin integrity are sensed by altered abundance of free MRTF (a G-actin-binding protein), which in turn regulates the transcription factor SRF (Olson and Nordheim 2010).…”

Section: Discussionmentioning

confidence: 99%

Evidence That an Unconventional Actin Can Provide Essential F-Actin Function and That a Surveillance System Monitors F-Actin Integrity in Chlamydomonas

2015

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Actin is one of the most conserved eukaryotic proteins. It is thought to have multiple essential cellular roles and to function primarily or exclusively as filaments ("F-actin"). Chlamydomonas has been an enigma, because a null mutation (ida5-1) in its single gene for conventional actin does not affect growth. A highly divergent actin gene, NAP1, is upregulated in ida5-1 cells, but it has been unclear whether NAP1 can form filaments or provide actin function. Here, we used the actin-depolymerizing drug latrunculin B (LatB), the F-actin-specific probe Lifeact-Venus, and genetic and molecular methods to resolve these issues. LatB-treated wild-type cells continue to proliferate; they initially lose Lifeact-stained structures but recover them concomitant with upregulation of NAP1. Thirty-nine LatB-sensitive mutants fell into four genes (NAP1 and LAT1-LAT3) in which we identified the causative mutations using a novel combinatorial pool-sequencing strategy. LAT1-LAT3 are required for NAP1 upregulation upon LatB treatment, and ectopic expression of NAP1 largely rescues the LatB sensitivity of the lat1-lat3 mutants, suggesting that the LAT gene products comprise a regulatory hierarchy with NAP1 expression as the major functional output. Selection of LatB-resistant revertants of a nap1 mutant yielded dominant IDA5 mutations that presumably render F-IDA5 resistant to LatB, and nap1 and lat mutations are synthetically lethal with ida5-1 in the absence of LatB. We conclude that both IDA5 and the divergent NAP1 can form filaments and redundantly provide essential F-actin functions and that a novel surveillance system, probably responding to a loss of F-actin, triggers NAP1 expression and perhaps other compensatory responses.

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YAPping about and not forgetting TAZ

et al. 2019

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The Hippo pathway has emerged as a major eukaryotic signalling pathway and is increasingly the subject of intense interest, as are the key effectors of canonical Hippo signalling, YES‐associated protein (YAP) and TAZ. The Hippo pathway has key roles in diverse biological processes, including network signalling regulation, development, organ growth, tissue repair and regeneration, cancer, stem cell regulation and mechanotransduction. YAP and TAZ are multidomain proteins and function as transcriptional coactivators of key genes to evoke their biological effects. YAP and TAZ interact with numerous partners and their activities are controlled by a complex set of processes. This review provides an overview of Hippo signalling and its role in growth. In particular, the functional domains of YAP and TAZ and the complex mechanisms that regulate their protein stability and activity are discussed. Notably, the similarities and key differences are highlighted between the two paralogues including which partner proteins interact with which functional domains to regulate their activity.

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Angiomotins link F-actin architecture to Hippo pathway signaling

Cited by 167 publications

References 27 publications

YAP Nuclear Localization in the Absence of Cell-Cell Contact Is Mediated by a Filamentous Actin-dependent, Myosin II- and Phospho-YAP-independent Pathway during Extracellular Matrix Mechanosensing

YAP Nuclear Localization in the Absence of Cell-Cell Contact Is Mediated by a Filamentous Actin-dependent, Myosin II- and Phospho-YAP-independent Pathway during Extracellular Matrix Mechanosensing

Evidence That an Unconventional Actin Can Provide Essential F-Actin Function and That a Surveillance System Monitors F-Actin Integrity in Chlamydomonas

YAPping about and not forgetting TAZ

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