a-raf kinase functions in arf6 regulated endocytic membrane traffic在arf6 a-raf激酶功能监管的内吞作用的膜流量.pdfVIP

A-RAF Kinase Functions in ARF6 Regulated Endocytic Membrane Traffic Elena Nekhoroshkova, Stefan Albert, Matthias Becker, Ulf R. Rapp* ¨ ¨ ¨ Institut fur Medizinische Strahlenkunde und Zellforschung (MSZ), University of Wurzburg, Wurzburg, Germany Abstract Background: RAF kinases direct ERK MAPK signaling to distinct subcellular compartments in response to growth factor stimulation. Methodology/Principal Findings: Of the three mammalian isoforms A-RAF is special in that one of its two lipid binding domains mediates a unique pattern of membrane localization. Specific membrane binding is retained by an N-terminal fragment (AR149) that corresponds to a naturally occurring splice variant termed DA-RAF2. AR149 colocalizes with ARF6 on tubular endosomes and has a dominant negative effect on endocytic trafficking. Moreover actin polymerization of yeast and mammalian cells is abolished. AR149/DA-RAF2 does not affect the internalization step of endocytosis, but trafficking to the recycling compartment. Conclusions/Significance: A-RAF induced ERK activation is required for this step by activating ARF6, as A-RAF depletion or inhibition of the A-RAF controlled MEK-ERK cascade blocks recycling. These data led to a new model for A-RAF function in endocytic trafficking. Citation: Nekhoroshkova E, Albert S, Becker M, Rapp UR (2009) A-RAF Kinase Functions in ARF6 Regulated Endocytic Membrane Traffic. PLoS ONE 4(2): e4647. doi:10.1371/journal.pone.0004647 Editor: Howard Riezman, University of Geneva, Switzerland Received July 15, 2008; Accepted January 13, 2009; Published February 27, 2009 Copyright: 2009 Nekhoroshkova et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, dis