Pdcd10-Stk24/25 complex controls kidney water reabsorption by regulating Aqp2 membrane targeting

JCI Insight. 2021 Jun 22;6(12):e142838. doi: 10.1172/jci.insight.142838.


PDCD10, also known as CCM3, is a gene found to be associated with the human disease cerebral cavernous malformations (CCMs). PDCD10 forms a complex with GCKIII kinases including STK24, STK25, and MST4. Studies in C. elegans and Drosophila have shown a pivotal role of the PDCD10-GCKIII complex in maintaining epithelial integrity. Here, we found that mice deficient of Pdcd10 or Stk24/25 in the kidney tubules developed polyuria and displayed increased water consumption. Although the expression levels of aquaporin genes were not decreased, the levels of total and phosphorylated aquaporin 2 (Aqp2) protein in the apical membrane of tubular epithelial cells were decreased in Pdcd10- and Stk24/25-deficient mice. This loss of Aqp2 was associated with increased expression and membrane targeting of Ezrin and phosphorylated Ezrin, Radixin, Moesin (p-ERM) proteins and impaired intracellular vesicle trafficking. Treatment with Erlotinib, a tyrosine kinase inhibitor promoting exocytosis and inhibiting endocytosis, normalized the expression level and membrane abundance of Aqp2 protein, and partially rescued the water reabsorption defect observed in the Pdcd10-deficient mice. Our current study identified the PDCD10-STK-ERM signaling pathway as a potentially novel pathway required for water balance control by regulating vesicle trafficking and protein abundance of AQP2 in the kidneys.

Keywords: Epithelial transport of ions and water; Mouse models; Nephrology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism*
  • Aquaporin 2 / genetics
  • Aquaporin 2 / metabolism*
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Kidney* / metabolism
  • Kidney* / physiology
  • Mice
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism
  • Water / metabolism*


  • Apoptosis Regulatory Proteins
  • Aqp2 protein, mouse
  • Aquaporin 2
  • Intracellular Signaling Peptides and Proteins
  • PDCD10 protein, mouse
  • Water
  • Stk24 protein, mouse
  • Stk25 protein, mouse
  • Protein Serine-Threonine Kinases