title: Regulation of mTOR by polycystin-1: is polycystic kidney disease a case of futile repair?
abstract: Recent work has uncovered a functional link between polycystin-1 (PC1), the protein affected in autosomal-dominant polycystic kidney disease (ADPKD) and tuberin, the protein affected in tuberous sclerosis complex (TSC). These data suggest that PC1 functions by inducing the formation of a complex with tuberin and the Ser/Thr kinase mTOR thereby inhibiting mTOR activity. In normal, adult kidney, mTOR is inactive. However, it is activated in response to insults and required for proliferative and hyperthrophic repair processes. We propose a model in which the PC1-tuberin-mTOR complex functions to sense renal insults, possibly by ciliary mechanotransduction, and regulates the activity of mTOR to trigger a formal repair program. In ADPKD, defects in PC1 would lead to constitutive activation of mTOR, and the affected cells would be engaged in a permanent state of futile repair leading to the formation and growth of renal cysts. The mTOR inhibitor rapamycin has proven highly effective in preventing and even reversing cyst growth in rodent models of polycystic kidney disease resulting in preservation of renal function. mTOR inhibitors, already in clinical use as immunosuppressants, may therefore be promising for future therapeutic approaches for ADPKD.
authors.affiliation: Molecular, Cellular, and Developmental Biology and Neuroscience Research Institute, University of California Santa Barbara, California 93106-9610, USA. weimbs@lifesci.ucsb.edu
authors.forename: Thomas
authors.initials: T
authors.lastname: Weimbs
mesh_terms: D000818:Animals; D005786:Gene Expression Regulation; D006801:Humans; D007668:Kidney / Q000293:injuries / Q000378:metabolism / Q000473:pathology; D008954:Models, Biological; D007690:Polycystic Kidney Diseases / Q000378:metabolism* / Q000473:pathology*; D011494:Protein Kinases / Q000096:biosynthesis* / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases; D050396:TRPP Cation Channels / Q000378:metabolism*; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D011494:Protein Kinases; D058570:TOR Serine-Threonine Kinases; D050396:TRPP Cation Channels; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; C000624653:TSC2 protein, human; C546842:MTOR protein, human