> For the complete documentation index, see [llms.txt](https://notes123.vladimir-vinarsky.me/llms.txt). Markdown versions of documentation pages are available by appending `.md` to page URLs; this page is available as [Markdown](https://notes123.vladimir-vinarsky.me/compounds/latrunculina.md).

# LatrunculinA

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## Latrunculin A

Latrunculin A is a drug which affects actin fibers polymerization by two mechanisms:

1\.         It sequesters the actin monomers, so the actin fibers cannot be formed (Spector et al. 1989)

2\.         it promotes dissociation of already established actin fibers (Fujiwara et al. 2018)

## Hippo and actin cytoskeleton

There are several papers showing the connection between actin cytoskeleton and Hippo pathway.\ <br>

1\.         Wada et al. in 2011 showed that F-actin cytoskeleton polymerization acts on Lats or upstream of Lats (Wada et al. 2011). In particular, F-actin stress fibers induce YAP1 localization, which can be inhibited by Cytochalasine D.

2\.         Aragona in 2013 show that that the F-actin inhibition can inhibit YAP1/TEAD activity independent of hippo (LATS1/2) (Aragona et al. 2013).

3\.         Dupont in 2011 shows that there is Hippo independent mechanical regulation through a Rho-kinase (Dupont et al. 2011).

4\.         Filamentous actin required for YAP1 nuclear localization in absence of cell-cell contact (Das et al. 2016).

## How does actin polymerization regulate YAP1 translocation?

1\.         The mechanism of F-actin stress fibers hippo interaction mechanism: They suggest that the Lats/Mst/Amot bind to F-actin and thus actin polymerization helps to increase Hippo signaling (Wada et al. 2011).

2\.         Aragona et al. 2013 shows effect of LatA and C3 on YAP1 localization in figure2. F-actin inhibitors (Cofilin1/2, Capzb, and Gelsolin) inhibit nuclear YAP1 localization (Aragona et al. 2013).

3\.         Rho-kinase activity inhibition (C3, LatA, Rock Inhibitor) independently on LATS inhibits nuclear localization of YAP1 mechanical regulation through a Rho-kinase (Dupont et al. 2011).

## Direct examples of LatrunculinA on YAP1 localization

1\.         Dupont et al. 2011 is directly showing that Latrunculin A inhibits nuclear localization of YAP1 (in figure 2).

2\.         LatrunculinA is understood to be a good inhibitor of YAP1/TEAD transcriptional activity, as it was used in another publication where they were looking for novel YAP1/TEAD inhibitor (BAY-593) through inhibition of RhoA-GTPase (Das et al. 2016)(Graham et al. biorxv 2023).

3\.         Nice comparison of Yap1 localization in MEFs and MCF10A cells treated with LatA, Blebb, Y-27632 (only LatA works in both, Blebb , Y-27632 does not work in MCF10A)

## Bibliography

Aragona, Mariaceleste, Tito Panciera, Andrea Manfrin, Stefano Giulitti, Federica Michielin, Nicola Elvassore, Sirio Dupont, and Stefano Piccolo. 2013. “A Mechanical Checkpoint Controls Multicellular Growth through YAP/TAZ Regulation by Actin-Processing Factors.” *Cell* 154 (5): 1047–59. <https://doi.org/10.1016/j.cell.2013.07.042>.

Das, Arupratan, Robert S. Fischer, Duojia Pan, and Clare M. Waterman. 2016. “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.” *The Journal of Biological Chemistry* 291 (12): 6096–6110. <https://doi.org/10.1074/jbc.M115.708313>.

Dupont, Sirio, Leonardo Morsut, Mariaceleste Aragona, Elena Enzo, Stefano Giulitti, Michelangelo Cordenonsi, Francesca Zanconato, et al. 2011. “Role of YAP/TAZ in Mechanotransduction.” *Nature* 474 (7350): 179–83. <https://doi.org/10.1038/nature10137>.

Fujiwara, Ikuko, Mark E Zweifel, Naomi Courtemanche, and Thomas D Pollard. 2018. “Latrunculin A Accelerates Actin Filament Depolymerization in Addition to Sequestering Actin Monomers.” *Current Biology* 28 (19): 3183-3192.e2. <https://doi.org/10.1016/j.cub.2018.07.082>.

Spector, I., N. R. Shochet, D. Blasberger, and Y. Kashman. 1989. “Latrunculins--Novel Marine Macrolides That Disrupt Microfilament Organization and Affect Cell Growth: I. Comparison with Cytochalasin D.” *Cell Motility and the Cytoskeleton* 13 (3): 127–44. <https://doi.org/10.1002/cm.970130302>.

Wada, Ken-Ichi, Kazuyoshi Itoga, Teruo Okano, Shigenobu Yonemura, and Hiroshi Sasaki. 2011. “Hippo Pathway Regulation by Cell Morphology and Stress Fibers.” *Development (Cambridge, England)* 138 (18): 3907–14. <https://doi.org/10.1242/dev.070987>.

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