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- Title
Hippo and PI5P4K signaling intersect to control the transcriptional activation of YAP.
- Authors
Palamiuc, Lavinia; Johnson, Jared L.; Haratipour, Zeinab; Loughran, Ryan M.; Choi, Woong Jae; Arora, Gurpreet K.; Tieu, Vivian; Ly, Kyanh; Llorente, Alicia; Crabtree, Sophia; Wong, Jenny C. Y.; Ravi, Archna; Wiederhold, Thorsten; Murad, Rabi; Blind, Raymond D.; Emerling, Brooke M.
- Abstract
Phosphoinositides are essential signaling molecules. The PI5P4K family of phosphoinositide kinases and their substrates and products, PI5P and PI4,5P2, respectively, are emerging as intracellular metabolic and stress sensors. We performed an unbiased screen to investigate the signals that these kinases relay and the specific upstream regulators controlling this signaling node. We found that the core Hippo pathway kinases MST1/2 phosphorylated PI5P4Ks and inhibited their signaling in vitro and in cells. We further showed that PI5P4K activity regulated several Hippo- and YAP-related phenotypes, specifically decreasing the interaction between the key Hippo proteins MOB1 and LATS and stimulating the YAP-mediated genetic program governing epithelial-to-mesenchymal transition. Mechanistically, we showed that PI5P interacted with MOB1 and enhanced its interaction with LATS, thereby providing a signaling connection between the Hippo pathway and PI5P4Ks. These findings reveal how these two important evolutionarily conserved signaling pathways are integrated to regulate metazoan development and human disease. Editor's summary: Activation of the Hippo pathway kinases results in the cytosolic retention of the transcriptional coactivator YAP, thereby preventing YAP from stimulating the expression of proliferation-promoting genes. Palamiuc et al. found that the phosphoinositide PI5P reinforced the inhibition of YAP by the Hippo pathway (see also the Focus by Hirsch et al.). Conversely, the Hippo pathway kinases phosphorylated and suppressed the activity of PI5P4Ks, the phosphoinositide kinases that metabolize PI5P to a phosphoinositide that did not inhibit YAP. In various human tumor types, increased expression of PI5P4K-encoding genes correlated with increased expression of a YAP gene signature associated with cancer progression. These results identify a signaling role for a phosphoinositide in supporting Hippo signaling. —Wei Wong
- Subjects
HIPPO signaling pathway; YAP signaling proteins; EPITHELIAL-mesenchymal transition; CELLULAR signal transduction; BIOCHEMICAL substrates
- Publication
Science Signaling, 2024, Vol 17, Issue 838, p1
- ISSN
1945-0877
- Publication type
Article
- DOI
10.1126/scisignal.ado6266