PHLPP1 regulates CFTR activity and lumen expansion through AMPK
Details
Publication Year 2022-10-15,Volume 149,Issue #20,Page dev200955.
Journal Title
Development
Abstract
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.
Publisher
COB
Keywords
*AMP-Activated Protein Kinases/genetics/metabolism; Animals; *Cystic Fibrosis Transmembrane Conductance Regulator/genetics/metabolism; Drosophila melanogaster/genetics/metabolism; Humans; Nuclear Proteins/genetics/metabolism; Phosphoprotein Phosphatases/genetics/metabolism; Phosphoric Monoester Hydrolases/metabolism; Phosphorylation; 3D culture; Ampk; Cftr; Epithelial; Lumenogenesis; Phlpp
WEHI Research Division(s)
Epigenetics And Development
PubMed ID
35997536
Open Access at Publisher's Site
https://doi.org/10.1242/dev.200955
Terms of Use/Rights Notice
Refer to copyright notice on published article.


Creation Date: 2022-08-30 09:11:25
Last Modified: 2022-08-30 09:15:47
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