TRAIL-death receptor endocytosis and apoptosis are selectively regulated by dynamin-1 activation

Carlos R. Reis, Ping Hung Chen, Nawal Bendris, Sandra L. Schmid

Research output: Contribution to journalArticlepeer-review

47 Scopus citations


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 apoptosisinducing 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.

Original languageEnglish (US)
Pages (from-to)504-509
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number3
StatePublished - Jan 17 2017


  • Calcineurin
  • Caspases
  • Clathrin-mediated endocytosis
  • Programmed cell death
  • Ryanodine receptor

ASJC Scopus subject areas

  • General


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