title: Activation of Rab8 guanine nucleotide exchange factor Rabin8 by ERK1/2 in response to EGF signaling.
abstract: Exocytosis is tightly regulated in many cellular processes, from neurite expansion to tumor proliferation. Rab8, a member of the Rab family of small GTPases, plays an important role in membrane trafficking from the trans-Golgi network and recycling endosomes to the plasma membrane. Rabin8 is a guanine nucleotide exchange factor (GEF) and major activator of Rab8. Investigating how Rabin8 is activated in cells is thus pivotal to the understanding of the regulation of exocytosis. Here we show that phosphorylation serves as an important mechanism for Rabin8 activation. We identified Rabin8 as a direct phospho-substrate of ERK1/2 in response to EGF signaling. At the molecular level, ERK phosphorylation relieves the autoinhibition of Rabin8, thus promoting its GEF activity. We further demonstrate that blocking ERK1/2-mediated phosphorylation of Rabin8 inhibits transferrin recycling to the plasma membrane. Together, our results suggest that ERK1/2 activate Rabin8 to regulate vesicular trafficking to the plasma membrane in response to extracellular signaling.
authors.affiliation: School of Life Sciences, Tsinghua University, Beijing 100084, People's Republic of China; Department of Biology, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Juanfei
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Biology, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Jinqi
authors.initials: J
authors.lastname: Ren
authors.affiliation: Department of Biology, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Bin
authors.initials: B
authors.lastname: Wu
authors.affiliation: Department of Biology, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Shanshan
authors.initials: S
authors.lastname: Feng
authors.affiliation: School of Life Sciences, Tsinghua University, Beijing 100084, People's Republic of China;
authors.forename: Guoping
authors.initials: G
authors.lastname: Cai
authors.affiliation: Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; and.
authors.forename: Florin
authors.initials: F
authors.lastname: Tuluc
authors.affiliation: Institute of Biotechnology, University of Helsinki, FIN 00014, Helsinki, Finland.
authors.forename: Johan
authors.initials: J
authors.lastname: Peränen
authors.affiliation: Department of Biology, University of Pennsylvania, Philadelphia, PA 19104; guowei@sas.upenn.edu.
authors.forename: Wei
authors.initials: W
authors.lastname: Guo
mesh_terms: D000595:Amino Acid Sequence; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D004705:Endocytosis / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000378:metabolism* / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D000081410:Germinal Center Kinases; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008969:Molecular Sequence Data; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D011487:Protein Conformation; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D015398:Signal Transduction / Q000187:drug effects; D014168:Transferrin / Q000378:metabolism; D020691:rab GTP-Binding Proteins / Q000378:metabolism*; D000099193:rab11 GTP-Binding Proteins
chemical_list: D004815:Epidermal Growth Factor; D048049:Extracellular Signal-Regulated MAP Kinases; D000081410:Germinal Center Kinases; D020662:Guanine Nucleotide Exchange Factors; D017346:Protein Serine-Threonine Kinases; D014168:Transferrin; D020691:rab GTP-Binding Proteins; D000099193:rab11 GTP-Binding Proteins
keywords: ERK; Rab GTPases; Rab8; guanine nucleotide exchange factor; phosphorylation