Failure to ubiquitinate c-Met leads to hyperactivation of mTOR signaling in a mouse model of autosomal dominant polycystic kidney disease
Shan Qin, … , Jing Zhou, Jordan A. Kreidberg
Shan Qin, … , Jing Zhou, Jordan A. Kreidberg
Published September 13, 2010
Citation Information: J Clin Invest. 2010;120(10):3617-3628. https://doi.org/10.1172/JCI41531.
View: Text | PDF
Research Article

Failure to ubiquitinate c-Met leads to hyperactivation of mTOR signaling in a mouse model of autosomal dominant polycystic kidney disease

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited disorder that is caused by mutations at two loci, polycystin 1 (PKD1) and polycystin 2 (PKD2). It is characterized by the formation of multiple cysts in the kidneys that can lead to chronic renal failure. Previous studies have suggested a role for hyperactivation of mammalian target of rapamycin (mTOR) in cystogenesis, but the etiology of mTOR hyperactivation has not been fully elucidated. In this report we have shown that mTOR is hyperactivated in Pkd1-null mouse cells due to failure of the HGF receptor c-Met to be properly ubiquitinated and subsequently degraded after stimulation by HGF. In Pkd1-null cells, Casitas B-lineage lymphoma (c-Cbl), an E3-ubiquitin ligase for c-Met, was sequestered in the Golgi apparatus with α3β1 integrin, resulting in the inability to ubiquitinate c-Met. Treatment of mouse Pkd1-null cystic kidneys in organ culture with a c-Met pharmacological inhibitor resulted in inhibition of mTOR activity and blocked cystogenesis in this mouse model of ADPKD. We therefore suggest that blockade of c-Met is a potential novel therapeutic approach to the treatment of ADPKD.

Authors

Shan Qin, Mary Taglienti, Surya M. Nauli, Leah Contrino, Ayumi Takakura, Jing Zhou, Jordan A. Kreidberg

×

Figure 6

Inhibition of Akt and S6K activity in vivo by c-Met inhibitor.

Options: View larger image (or click on image) Download as PowerPoint
Inhibition of Akt and S6K activity in vivo by c-Met inhibitor. Different...
Differential localization in vivo for α3β1 integrin and c-Cbl in WT and Pkd1–/– mouse kidneys. (A) Costaining for α3 integrin and c-Cbl. (B) Costaining for β1 integrin and c-Cbl. In each panel, the genotype is noted in the upper-left corner, and the stain is noted above. The third panel in each row shows an overlay, with a magnified image (×600) in the fourth panel. α3β1 integrin is present in a basolateral distribution in WT and a cytoplasmic distribution in the Pkd1–/– tubules. c-Cbl has a basal distribution in WT and cytoplasmic localization that overlaps with α3β1 integrin in Pkd1–/– tubules. (C) Staining for c-Cbl and α3β1 integrin in human non-cystic and PKD kidneys, showing basolateral localization of c-Cbl and α3β1 integrin in the non-PKD sample and perinuclear pattern in the PKD sample. Scale bars: 50 μm.