title: TRAIL-death receptor endocytosis and apoptosis are selectively regulated by dynamin-1 activation.
abstract: Clathrin-mediated endocytosis (CME) constitutes the major pathway for uptake of signaling receptors into eukaryotic cells. As such, CME regulates signaling from cell-surface receptors, but whether and how specific signaling receptors reciprocally regulate the CME machinery remains an open question. Although best studied for its role in membrane fission, the GTPase dynamin also regulates early stages of CME. We recently reported that dynamin-1 (Dyn1), previously assumed to be neuron-specific, can be selectively activated in cancer cells to alter endocytic trafficking. Here we report that dynamin isoforms differentially regulate the endocytosis and apoptotic signaling downstream of TNF-related apoptosis-inducing ligand-death receptor (TRAIL-DR) complexes in several cancer cells. Whereas the CME of constitutively internalized transferrin receptors is mainly dependent on the ubiquitously expressed Dyn2, TRAIL-induced DR endocytosis is selectively regulated by activation of Dyn1. We show that TRAIL stimulation activates ryanodine receptor-mediated calcium release from endoplasmic reticulum stores, leading to calcineurin-mediated dephosphorylation and activation of Dyn1, TRAIL-DR endocytosis, and increased resistance to TRAIL-induced apoptosis. TRAIL-DR-mediated ryanodine receptor activation and endocytosis is dependent on early caspase-8 activation. These findings delineate specific mechanisms for the reciprocal crosstalk between signaling and the regulation of CME, leading to autoregulation of endocytosis and signaling downstream of surface receptors.
authors.affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Carlos R
authors.initials: CR
authors.lastname: Reis
authors.affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Ping-Hung
authors.initials: PH
authors.lastname: Chen
authors.affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Nawal
authors.initials: N
authors.lastname: Bendris
authors.affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390 sandra.schmid@utsouthwestern.edu.
authors.forename: Sandra L
authors.initials: SL
authors.lastname: Schmid
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D020013:Calcium Signaling; D053181:Caspase 8 / Q000378:metabolism; D045744:Cell Line, Tumor; D002966:Clathrin / Q000378:metabolism; D034284:Dynamin I / Q000378:metabolism*; D004705:Endocytosis / Q000502:physiology*; D006801:Humans; D008954:Models, Biological; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D015398:Signal Transduction; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*
chemical_list: D002966:Clathrin; D019837:Ryanodine Receptor Calcium Release Channel; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C505530:CASP8 protein, human; D053181:Caspase 8; D034284:Dynamin I
keywords: calcineurin; caspases; clathrin-mediated endocytosis; programmed cell death; ryanodine receptor