LatrunculinA

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C:\Users\vld\Documents\MANUSCRIPT-YAP1\RESOURCES\notes-LatA.docx

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.

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.