Hippo pathway regulation by phosphatidylinositol transfer protein and phosphoinositides

  • Nat Chem Biol. 2022 Oct;18(10):1076-1086. doi: 10.1038/s41589-022-01061-z.
Fu-Long Li   #  1  2 ,  Vivian Fu   #  1  2 ,  Guangbo Liu   #  1  2 ,  Tracy Tang  3 ,  Andrei W Konradi  3 ,  Xiao Peng  3  4 ,  Esther Kemper  5 ,  Benjamin F Cravatt  5 ,  J Matthew Franklin  1  2 ,  Zhengming Wu  1  2 ,  Joshua Mayfield  1 ,  Jack E Dixon  1 ,  William H Gerwick  6 ,  Kun-Liang Guan  7  8
Affiliations
  • 1. Department of Pharmacology, University of California San Diego, La Jolla, CA, USA.
  • 2. Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
  • 3. Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California San Diego, La Jolla, CA, USA.
  • 4. Vivace Therapeutics, Inc., San Mateo, CA, USA.
  • 5. Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.
  • 6. Genus IntelliGen, Windsor, WI, USA.
  • 7. Department of Pharmacology, University of California San Diego, La Jolla, CA, USA. [email protected].
  • 8. Moores Cancer Center, University of California San Diego, La Jolla, CA, USA. [email protected].
  • # Contributed equally.
PMID: 35788180 DOI: 10.1038/s41589-022-01061-z
Abstract

The Hippo pathway plays a key role in development, organ size control and tissue homeostasis, and its dysregulation contributes to Cancer. The LATS tumor suppressor kinases phosphorylate and inhibit the YAP/TAZ transcriptional co-activators to suppress gene expression and cell growth. Through a screen of Marine natural products, we identified microcolin B (MCB) as a Hippo activator that preferentially kills YAP-dependent Cancer cells. Structure-activity optimization yielded more potent MCB analogs, which led to the identification of phosphatidylinositol transfer proteins α and β (PITPα/β) as the direct molecular targets. We established a critical role of PITPα/β in regulating LATS and YAP. Moreover, we showed that PITPα/β influence the Hippo pathway via plasma membrane phosphatidylinositol-4-phosphate. This study uncovers a previously unrecognized role of PITPα/β in Hippo pathway regulation and as potential Cancer therapeutic targets.

Products