Angiomotins link Hippo signaling to the actin cytoskeleton.

Cells rapidly remodel their actin cytoskeleton to deal with mechanical strain. Hippo signaling is strongly regulated by changes in actin organization. Thus the Hippo pathway appears to indirectly sense mechanical strain by monitoring the actin cytoskeleton. We identified the first direct connection between the Hippo pathway and the actin cytoskeleton. We showed that angiomotins are novel Hippo pathway scaffolding proteins that interact with both F-actin and multiple core components of the signaling network. Angiomotins inhibit YAP, a transcriptional co-activator that is the primary effector of Hippo signaling through two mechanisms; directly binding YAP and sequestering it in the cytoplasm, and by activating the YAP inhibitory kinase LATS. We showed that F-actin and YAP compete for binding to angiomotins rendering angiomotin inhibition of YAP sensitive to F-actin levels. Ongoing studies in the lab focus on how angiomotins activate LATS, and how this activation is regulated by F-actin.

Relevant Publications:

Mana-Capelli S, Paramasivam M, Dutta S, McCollum D. Angiomotins link F-actin architecture to Hippo pathway signaling. Mol Biol Cell. 2014;25(10):1676-85. Epub 2014/03/22. doi: 10.1091/mbc.E13-11-0701mbc.E13-11-0701 [pii]. PubMed PMID: 24648494; PMCID: PMC4019498.

Mana-Capelli S, McCollum D. Angiomotins stimulate LATS kinase autophosphorylation and act as scaffolds that promote Hippo signaling. J Biol Chem. 2018;293(47):18230-41. Epub 2018/09/30. doi: 10.1074/jbc.RA118.004187. PubMed PMID: 30266805; PMCID: PMC6254346.