title: Extracellular signal-regulated kinase regulates clathrin-independent endosomal trafficking.
abstract: Extracellular signal-regulated kinase (Erk) is widely recognized for its central role in cell proliferation and motility. Although previous work has shown that Erk is localized at endosomal compartments, no role for Erk in regulating endosomal trafficking has been demonstrated. Here, we report that Erk signaling regulates trafficking through the clathrin-independent, ADP-ribosylation factor 6 (Arf6) GTPase-regulated endosomal pathway. Inactivation of Erk induced by a variety of methods leads to a dramatic expansion of the Arf6 endosomal recycling compartment, and intracellular accumulation of cargo, such as class I major histocompatibility complex, within the expanded endosome. Treatment of cells with the mitogen-activated protein kinase kinase (MEK) inhibitor U0126 reduces surface expression of MHCI without affecting its rate of endocytosis, suggesting that inactivation of Erk perturbs recycling. Furthermore, under conditions where Erk activity is inhibited, a large cohort of Erk, MEK, and the Erk scaffold kinase suppressor of Ras 1 accumulates at the Arf6 recycling compartment. The requirement for Erk was highly specific for this endocytic pathway, because its inhibition had no effect on trafficking of cargo of the classical clathrin-dependent pathway. These studies reveal a previously unappreciated link of Erk signaling to organelle dynamics and endosomal trafficking.
authors.affiliation: Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Robertson
authors.forename: Subba Rao Gangi
authors.initials: SR
authors.lastname: Setty
authors.forename: Anand
authors.initials: A
authors.lastname: Sitaram
authors.forename: Michael S
authors.initials: MS
authors.lastname: Marks
authors.forename: Robert E
authors.initials: RE
authors.lastname: Lewis
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Chou
mesh_terms: D000089982:ADP-Ribosylation Factor 6; D020727:ADP-Ribosylation Factors / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D015415:Biomarkers; D002070:Butadienes / Q000494:pharmacology; D002462:Cell Membrane / Q000378:metabolism; D002966:Clathrin / Q000502:physiology*; D004705:Endocytosis / Q000187:drug effects / Q000502:physiology*; D011992:Endosomes / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004843:Epistasis, Genetic; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D006367:HeLa Cells; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D048369:MAP Kinase Kinase 1 / Q000032:analysis; D009570:Nitriles / Q000494:pharmacology; D011494:Protein Kinases / Q000032:analysis / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000089982:ADP-Ribosylation Factor 6; D015415:Biomarkers; D002070:Butadienes; D002966:Clathrin; D004791:Enzyme Inhibitors; D015395:Histocompatibility Antigens Class I; D009570:Nitriles; C113580:U 0126; D011494:Protein Kinases; C097199:KSR-1 protein kinase; D048049:Extracellular Signal-Regulated MAP Kinases; D048369:MAP Kinase Kinase 1; D020727:ADP-Ribosylation Factors; C000715348:ARF6 protein, human