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.
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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

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Figure 7

A c-Met inhibitor decreased the size and number of cysts in Pkd1–/– kidneys.

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A c-Met inhibitor decreased the size and number of cysts in Pkd1–/– kidn...
(A) Treatment in an organ culture model of PKD. The genotype and treatment are noted on the left and above the panels, respectively. Pkd1+/+ and Pkd1–/– mice kidneys at E15.5 were removed from embryonic mice and put in organ culture dishes, containing media with 10 μM 8-Br-cAMP. Twelve hours later, either 5 μM c-Met inhibitor Su11274 (dissolved in DMSO) or the same amount of DMSO was added to the media. Hematoxylin and eosin–stained sections of kidneys are shown after 96 hours of treatment. Scale bars: 200 μm. (B) Treatment of pregnant mice with c-Met inhibitor. Pkd1+/– pregnant mice that had been mated with Pkd1+/– male mice were treated twice daily between E14 and E17 with vehicle only (top row) or c-Met inhibitor (bottom row). c-Met inhibitor treatment can decrease cyst formation in Pkd1–/– embryonic kidneys. A high-power view is shown at right. (C) Kidney development in utero in WT kidneys was not affected by treatment with c-Met inhibitor. Top panels: WT kidney from vehicle-only treatment; bottom panels: WT kidney from c-Met inhibitor–treated litter. Scale bars in B and C: 200 μm (left), 50 μm (right). (D) Quantitative analysis of cystic area in Pkd1–/– embryonic kidneys treated with vehicle or c-Met inhibitor. Kidneys from 9 pairs of vehicle and c-Met inhibitor–treated mice were quantified by NIS-Elements BR. The difference in cyst area between vehicle- and c-Met inhibitor–treated group is significant (*P = 0.003), as analyzed by paired Student’s t test.