carboxy terminal tail of polycystin-1 regulates localization of tsc2 to repress mtor羧基末端尾巴抑制mtor tsc2 polycystin-1调节定位的.pdfVIP

Carboxy Terminal Tail of Polycystin-1 Regulates Localization of TSC2 to Repress mTOR 1 2 3 1 Ruhee Dere , Patricia D. Wilson , Richard N. Sandford , Cheryl Lyn Walker * 1 Department of Carcinogenesis, University of Texas M.D. Anderson Cancer Center, Smithville, Texas, United States of America, 2 Department of Pediatrics, Children’s Research Institute, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America, 3 Department of Medical Genetics, University of Cambridge, Cambridge, United Kingdom Abstract Autosomal dominant polycystic kidney disease (ADPKD) is a commonly inherited renal disorder caused by defects in the PKD1 or PKD2 genes. ADPKD is associated with significant morbidity, and is a major underlying cause of end-stage renal failure (ESRF). Commonly, treatment options are limited to the management of hypertension, cardiovascular risk factors, dialysis, and transplantation when ESRF develops, although several new pharmacotherapies, including rapamycin, have shown early promise in animal and human studies. Evidence implicates polycystin-1 (PC-1), the gene product of the PKD1 gene, in regulation of the mTOR pathway. Here we demonstrate a mechanism by which the intracellular, carboxy-terminal tail of polycystin-1 (CP1) regulates mTOR signaling by altering the subcellular localization of the tuberous sclerosis complex 2 (TSC2) tumor suppressor, a gatekeeper for mTOR activity. Phosphorylation of TSC2 at S939 by AKT causes partitioning of TSC2 away from the membrane, its GAP target Rheb, and its activating partner TSC1 to the cytosol via 14-3-3 protein binding. We found that TSC2 and a C-terminal polycystin-1 peptide (CP1) directly interact and that a membrane-tethered CP1 protects TSC2 from AKT phosphorylation at S939, re