PHLPP1 regulates CFTR activity and lumen expansion through AMPK

Development. 2022 Oct 15;149(20):dev200955. doi: 10.1242/dev.200955. Epub 2022 Aug 23.


Complex organ development depends on single lumen formation and its expansion during tubulogenesis. This can be achieved by correct mitotic spindle orientation during cell division, combined with luminal fluid filling that generates hydrostatic pressure. Using a human 3D cell culture model, we have identified two regulators of these processes. We find that pleckstrin homology leucine-rich repeat protein phosphatase (PHLPP) 2 regulates mitotic spindle orientation, and thereby midbody positioning and maintenance of a single lumen. Silencing the sole PHLPP family phosphatase in Drosophila melanogaster, phlpp, resulted in defective spindle orientation in Drosophila neuroblasts. Importantly, cystic fibrosis transmembrane conductance regulator (CFTR) is the main channel regulating fluid transport in this system, stimulated by phosphorylation by protein kinase A and inhibited by the AMP-activated protein kinase AMPK. During lumen expansion, CFTR remains open through the action of PHLPP1, which stops activated AMPK from inhibiting ion transport through CFTR. In the absence of PHLPP1, the restraint on AMPK activity is lost and this tips the balance in the favour of channel closing, resulting in the lack of lumen expansion and accumulation of mucus.

Keywords: 3D culture; AMPK; CFTR; Epithelial; Lumenogenesis; PHLPP.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases* / genetics
  • AMP-Activated Protein Kinases* / metabolism
  • Animals
  • Cystic Fibrosis Transmembrane Conductance Regulator* / genetics
  • Cystic Fibrosis Transmembrane Conductance Regulator* / metabolism
  • Drosophila melanogaster / genetics
  • Drosophila melanogaster / metabolism
  • Humans
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Phosphoprotein Phosphatases / genetics
  • Phosphoprotein Phosphatases / metabolism
  • Phosphoric Monoester Hydrolases / metabolism
  • Phosphorylation


  • CFTR protein, human
  • Nuclear Proteins
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • AMP-Activated Protein Kinases
  • PHLPP1 protein, human
  • Phosphoprotein Phosphatases
  • Phosphoric Monoester Hydrolases