Ciliary transport regulates PDGF-AA/   signaling via elevated mammalian target of rapamycin signaling and diminished PP2A activity

• Type of Material: Article
• Authors: Nicole L. Umberger, Emory University; Tamara Caspary, Emory University
• Language: English
• Date: 2015-01-15
• Publisher: American Society for Cell Biology
• Publication Version: Final Published Version
• Copyright Statement: © 2015 Umberger and Caspary.
• License: Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.1091/mbc.E14-05-0952
• Title of Journal or Parent Work: Molecular Biology of the Cell
• ISSN: 1059-1524
• Volume: 26
• Issue: 2
• Start Page: 350
• End Page: 358
• Grant/Funding Information: This research project was supported with research funding from the Muscular Dystrophy Association (131071), National Institute of Neurological Disorders and Stroke (NINDS; R01 NS056380), and Emory Neuroscience NINDS Core Facilities (P30NS055077—Emory University Integrated Cellular Imaging Microscopy Core). N.L.U. was supported by an Emory PRISM Graduate Teaching Fellows in K–12 Education Fellowship (DGE0536941), an Emory Genetics and Molecular Biology Graduate Program Training Grant (T32GM008490), and an Emory Human Disease Genetics Training Fellowship (T32MH087977).
• Research Categories: Biology, Genetics; Health Sciences, General

Abstract

Primary cilia are built and maintained by intraflagellar transport (IFT), whereby the two IFT complexes, IFTA and IFTB, carry cargo via kinesin and dynein motors for anterograde and retrograde transport, respectively. Many signaling pathways, including platelet- derived growth factor (PDGF)-AA/αα, are linked to primary cilia. Active PDGF-AA/αα signaling results in phosphorylation of Akt at two residues: P-AktT308 and P-AktS473, and previous work showed decreased P-AktS473 in response to PDGF-AA upon anterograde transport disruption. In this study, we investigated PDGF-AA/αα signaling via P-AktT308 and P-AktS473 in distinct ciliary transport mutants. We found increased Akt phosphorylation in the absence of PDGF-AA stimulation, which we show is due to impaired dephosphorylation resulting from diminished PP2A activity toward P-AktT308. Anterograde transport mutants display low platelet-derived growth factor receptor (PDGFR)α levels, whereas retrograde mutants exhibit normal PDGFRα levels. Despite this, neither shows an increase in P-AktS473 or P-AktT308 upon PDGF-AA stimulation. Because mammalian target of rapamycin complex 1 (mTORC1) signaling is increased in ciliary transport mutant cells and mTOR signaling inhibits PDGFRα levels, we demonstrate that inhibition of mTORC1 rescues PDGFRα levels as well as PDGF-AA–dependent phosphorylation of AktS473 and AktT308 in ciliary transport mutant MEFs. Taken together, our data indicate that the regulation of mTORC1 signaling and PP2A activity by ciliary transport plays key roles in PDGF-AA/αα signaling.