Abstract
Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disease characterized by the formation of renal cysts. This disease can be caused by mutations in two genes, PKD1 and PKD2, which encode polycystin-1 (PC-1) and -2 (PC-2), respectively.PC-1 is a large plasma membrane receptor involved in the regulation of several biological functions and signaling pathways, and PC-2 is a calcium channel of the TRP family. The two proteins associate in a complex to prevent cyst formation, but the precise mechanism(s) involved remain largely unknown.This review will focus on recent advances in our understanding of the functions of polycystins and their role in signal transduction.Increased activity of the mammalian target of rapamycin (mTOR) kinase has been observed in cysts found in ADPKD tissues. Rapamycin has been shown to have beneficial effects in rodent models of polycystic kidney disease, prompting the initiation of pilot clinical trials with human patients. Furthermore, a direct role for PC-1 in the regulation of cell growth (size) via mTOR has recently been demonstrated.Major advancements in the study of mTOR biology have highlighted that this kinase exists in association with two different complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). The mTORC1 complex regulates cell growth (size), proliferation, translation and autophagy, and mTORC2 regulates the actin cytoskeleton and apoptosis. Interestingly, mTORC2 has been shown to contain the kinase responsible for the phosphorylation of Akt at Serine 473. Previous studies have shown that PC-1 controls the PI 3-kinase/Akt cascade to regulate apoptosis and the actin cytoskeleton, suggesting that this receptor might regulate mTOR at several levels.This review aims to discuss three different, inter-related themes emerging from the literature: (i) studies performed in our and other laboratories collectively suggest that PC-1 might be able to differentially regulate the two mTOR complexes; (ii) several studies point to genetic and functional cross-talk between the PKD and TSC genes, although the molecular details remain obscure; and (iii) studies performed in mammals and in the unicellular algae Chlamidomonas Reinhardtii might highlight a link between cilia, regulation of cell size and regulation of the cell cycle.
Highlights
Increased activity of the mammalian target of rapamycin kinase has been observed in cysts found in Autosomal dominant polycystic kidney disease (ADPKD) tissues
Major advancements in the study of mammalian target of rapamycin (mTOR) biology have highlighted that this kinase exists in association with two different complexes, mTOR complex 1 and mTOR complex 2
This review aims to discuss three different, inter-related themes emerging from the literature: (i) studies performed in our and other laboratories collectively suggest that PC-1 might be able to differentially regulate the two mTOR complexes; (ii) several studies point to genetic and functional cross-talk between the PKD and Tuberous Sclerosis Complex (TSC) genes, the molecular details remain obscure; and (iii) studies performed in mammals and in the unicellular algae Chlamidomonas Reinhardtii might highlight a link between cilia, regulation of cell size and regulation of the cell cycle
Summary
Recent studies have uncovered important roles for Polycystin-1 in the regulation of the mTOR cascades and its complexes Have these studies shown the potential of using a well-characterized drug, rapamycin, to slow disease progression in ADPKD, but they have uncovered important new functions of the polycystins. There is currently no answer to this question, but it cannot be ignored that besides the TORC1 pathway, the other known cascade involved in the regulation of cell/tissue size is that of the Hippo pathway [126]. It is intuitive that these pathways need to be coordinated in order to achieve and maintain proper tissue morphogenesis This link might be regulated by the primary cilium and could be disrupted in cystic kidney diseases or other disorders such as cancer. ADPKD: autosomal dominant polycystic kidney disease; AMPK: AMP-dependent protein kinase; AP-1: activator protein 1; DEPTOR: DEP domains interactor of mTOR; eIF4: eukaryotic translation initiation factor 4; eIF2: eukaryotic translation initiation factor 2; ER: endoplasmic reticulum; ERK: extracellular regulated kinase; FKBP12: FK506-binding protein 12; FKHR: forkhead rabdomyosarcoma; FOXO: Forkhead box class O; GAP: GTPase-activating protein; GEF: guanine-nucleotide exchange factor; GPS: G-protein coupled proteolytic site; GSK3β: glycogene synthase kinase β; IFT: intra-flagellar transport; IRS: insulin receptor substrate; JAK: Janus kinase; LST8: lethal with SEC13 protein 8; MDCK: Madin Darby kidney cells; mTOR: mammalian target of rapamycin; NFAT: nuclear factor of activated T-cells; NIMA: never in mitosis; PCP: planar cell polarity; PDK1: phosphatidylinositol-dependent kinase 1; PERK: PKR-like ER kinase; PH domain: plecstrin homology domain; PI3K: phosphoinositide 3kinase; PKCα: protein kinase Cα; PRAS40: proline rich Akt substrate; Protor: protein observed with rictor-1; Rag: Ras related GTPase; Raptor: regulatory associated protein of mTOR; REDD1: DNA damage response 1; Rheb: Ras homologue enriched in brain; Rictor: rapamycin-insensitive companion of mTOR; RSK: p90 ribosomal protein S6 kinase; SGK1: serum- and glucocorticoid-induced kinase 1; STAT: signal transducers and activators of transcription; S6K: 70 kDa ribosomal protein S6 kinase; TRPL: transient receptor potential; TSC: tuberous sclerosis complex; 4EBP1: eukaryotic-translation-initiation-factor-4E-binding protein 1
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
