RRC ID 45859
著者 Skorobogata O, Escobar-Restrepo JM, Rocheleau CE.
タイトル An AGEF-1/Arf GTPase/AP-1 ensemble antagonizes LET-23 EGFR basolateral localization and signaling during C. elegans vulva induction.
ジャーナル PLoS Genet
Abstract LET-23 Epidermal Growth Factor Receptor (EGFR) signaling specifies the vulval cell fates during C. elegans larval development. LET-23 EGFR localization on the basolateral membrane of the vulval precursor cells (VPCs) is required to engage the LIN-3 EGF-like inductive signal. The LIN-2 Cask/LIN-7 Veli/LIN-10 Mint (LIN-2/7/10) complex binds LET-23 EGFR, is required for its basolateral membrane localization, and therefore, vulva induction. Besides the LIN-2/7/10 complex, the trafficking pathways that regulate LET-23 EGFR localization have not been defined. Here we identify vh4, a hypomorphic allele of agef-1, as a strong suppressor of the lin-2 mutant Vulvaless (Vul) phenotype. AGEF-1 is homologous to the mammalian BIG1 and BIG2 Arf GTPase guanine nucleotide exchange factors (GEFs), which regulate secretory traffic between the Trans-Golgi network, endosomes and the plasma membrane via activation of Arf GTPases and recruitment of the AP-1 clathrin adaptor complex. Consistent with a role in trafficking we show that AGEF-1 is required for protein secretion and that AGEF-1 and the AP-1 complex regulate endosome size in coelomocytes. The AP-1 complex has previously been implicated in negative regulation of LET-23 EGFR, however the mechanism was not known. Our genetic data indicate that AGEF-1 is a strong negative regulator of LET-23 EGFR signaling that functions in the VPCs at the level of the receptor. In line with AGEF-1 being an Arf GEF, we identify the ARF-1.2 and ARF-3 GTPases as also negatively regulating signaling. We find that the agef-1(vh4) mutation results in increased LET-23 EGFR on the basolateral membrane in both wild-type and lin-2 mutant animals. Furthermore, unc-101(RNAi), a component of the AP-1 complex, increased LET-23 EGFR on the basolateral membrane in lin-2 and agef-1(vh4); lin-2 mutant animals. Thus, an AGEF-1/Arf GTPase/AP-1 ensemble functions opposite the LIN-2/7/10 complex to antagonize LET-23 EGFR basolateral membrane localization and signaling.
巻・号 10(10)
ページ e1004728
公開日 2014-10-1
DOI 10.1371/journal.pgen.1004728
PII PGENETICS-D-14-01751
PMID 25329472
PMC PMC4199573
MeSH Amino Acid Sequence Animals Animals, Genetically Modified Caenorhabditis elegans / genetics Caenorhabditis elegans / metabolism Caenorhabditis elegans / physiology* Caenorhabditis elegans Proteins / genetics Caenorhabditis elegans Proteins / metabolism* Cell Membrane / metabolism ErbB Receptors / genetics ErbB Receptors / metabolism* Female GTP Phosphohydrolases / genetics GTP Phosphohydrolases / metabolism Genes, Suppressor Guanine Nucleotide Exchange Factors / genetics Guanine Nucleotide Exchange Factors / metabolism* Humans Intestinal Mucosa / metabolism Larva / metabolism Lysosomes / genetics Lysosomes / pathology Molecular Sequence Data Multiprotein Complexes / metabolism Sequence Homology, Amino Acid Signal Transduction Vulva / cytology Vulva / growth & development* Vulva / metabolism
IF 5.175
引用数 9
WOS 分野 GENETICS & HEREDITY
リソース情報
線虫 tm3767 tm1693 tm1877 tm1447