2. Academic Validation
  3. Hippo pathway regulation by phosphatidylinositol transfer protein and phosphoinositides

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

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. kuguan@ucsd.edu.
  • 8 Moores Cancer Center, University of California San Diego, La Jolla, CA, USA. kuguan@ucsd.edu.
  • # 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.

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