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

J Clin Invest. 2010 Oct;120(10):3617-28. doi: 10.1172/JCI41531. Epub 2010 Sep 13.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cilia / physiology
  • Disease Models, Animal
  • Glycosylation
  • Golgi Apparatus / physiology
  • Integrin alpha3beta1 / metabolism
  • Intracellular Signaling Peptides and Proteins / physiology*
  • Mice
  • Morphogenesis
  • Polycystic Kidney, Autosomal Dominant / metabolism*
  • Protein-Serine-Threonine Kinases / physiology*
  • Proto-Oncogene Proteins c-cbl / metabolism
  • Proto-Oncogene Proteins c-met / antagonists & inhibitors
  • Proto-Oncogene Proteins c-met / metabolism*
  • Signal Transduction / physiology*
  • TOR Serine-Threonine Kinases
  • TRPP Cation Channels / physiology
  • Ubiquitination*

Substances

  • Integrin alpha3beta1
  • Intracellular Signaling Peptides and Proteins
  • TRPP Cation Channels
  • polycystic kidney disease 1 protein
  • Proto-Oncogene Proteins c-cbl
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Proto-Oncogene Proteins c-met
  • Protein-Serine-Threonine Kinases
  • Cbl protein, mouse