Department of Biochemistry and Molecular Pharmacology
Amino Acids, Peptides, and Proteins | Biochemistry | Cell Biology | Cells | Enzymes and Coenzymes
The Hippo pathway controls cell proliferation, differentiation, and survival by regulating the 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 the kinase domain by MST1/2 and other kinases. Phosphorylation of the HM motif then triggers autophosphorylation of the kinase in the activation loop (AL) 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 AL 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.
AMOT, Angiomotin, Hippo pathway, LATS (Warts, Wts), MOB1, MST1 (Mammalian Sterile 20-like kinase 1), MST2 (Mammalian Sterile 20-like kinase 2), SAV1, Salvador (sav), cell signaling, mechanotransduction, protein kinase, scaffold protein, yes-associated protein (YAP)
Rights and Permissions
Copyright the Authors under license to ASBMB. Accepted manuscript published as allowed by publisher's license at http://www.jbc.org/site/misc/edpolicy.xhtml#copyright.
DOI of Published Version
J Biol Chem. 2018 Sep 28. pii: RA118.004187. doi: 10.1074/jbc.RA118.004187. [Epub ahead of print] Link to article on publisher's site
The Journal of biological chemistry
Mana-Capelli S, McCollum D. (2018). Angiomotins stimulate LATS kinase autophosphorylation and act as scaffolds that promote Hippo signaling. Open Access Articles. https://doi.org/10.1074/jbc.RA118.004187. Retrieved from https://escholarship.umassmed.edu/oapubs/3602