The cytoplasmic tail of FPC antagonizes the full-length protein in the regulation of mTOR pathway

Shixuan Wang, Maoqing Wu, Gang Yao, Jingjing Zhang, Jing Zhou

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

FPC (fibrocystin or polyductin) is a single transmembrane receptor-like protein, responsible for the human autosomal recessive polycystic kidney disease (ARPKD). It was recently proposed that FPC undergoes a Notch-like cleavage and subsequently the cleaved carboxy(C)-terminal fragment translocates to the nucleus. To study the functions of the isolated C-tail, we expressed the intracellular domain of human FPC (hICD) in renal epithelial cells. By 3-dimensional (3D) tubulogenesis assay, we found that in contrast to tubule-like structures formed from control cells, hICD-expressing cells exclusively formed cyst-like structures. By western blotting, we showed that the Akt/mTOR pathway, indicated by increased phosphorylation of Akt at serine 473 and S6 kinase 1 at threonine 389, was constitutively activated in hICD-expressing cells, similar to that in FPC knockdown cells and ARPKD kidneys. Moreover, application of mTOR inhibitor rapamycin reduced the size of the cyst-like structures formed by hICD-expressing cells. Application of either LY294002 or wortmannin inhibited the activation of both S6K1 and Akt. Expression of full-length FPC inhibited the activation of S6 and S6 kinase whereas co-expression of hICD with full-length FPC antagonized the inhibitory effect of full-length FPC on mTOR. Taken together, we propose that FPC modulates the PI3K/Akt/mTOR pathway and the cleaved C-tail regulates the function of the full-length protein.

Original languageEnglish (US)
Article numbere95630
JournalPloS one
Volume9
Issue number5
DOIs
StatePublished - May 22 2014

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Ribosomal Protein S6 Kinases
Tail
tail
Chemical activation
Autosomal Recessive Polycystic Kidney
Phosphorylation
Sirolimus
Threonine
Phosphatidylinositol 3-Kinases
Serine
Assays
Proteins
proteins
cells
Cysts
phosphotransferases (kinases)
Kidney
S 6
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Protein-Serine-Threonine Kinases

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

The cytoplasmic tail of FPC antagonizes the full-length protein in the regulation of mTOR pathway. / Wang, Shixuan; Wu, Maoqing; Yao, Gang; Zhang, Jingjing; Zhou, Jing.

In: PloS one, Vol. 9, No. 5, e95630, 22.05.2014.

Research output: Contribution to journalArticle

Wang, Shixuan ; Wu, Maoqing ; Yao, Gang ; Zhang, Jingjing ; Zhou, Jing. / The cytoplasmic tail of FPC antagonizes the full-length protein in the regulation of mTOR pathway. In: PloS one. 2014 ; Vol. 9, No. 5.
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