title: SEPT9 negatively regulates ubiquitin-dependent downregulation of EGFR.
abstract: Septins constitute a family of GTP-binding proteins that are involved in a variety of biological processes. Several isoforms have been implicated in disease, but the molecular mechanisms underlying pathogenesis are poorly understood. Here, we show that depletion of SEPT9 decreases surface levels of epidermal growth factor receptors (EGFRs) by enhancing receptor degradation. We identify a consensus motif within the SEPT9 N-terminal domain that supports its association with the adaptor protein CIN85 (also known as SH3KBP1). We further show CIN85-SEPT9 to be localized exclusively to the plasma membrane, where SEPT9 is recruited to EGF-engaged receptors in a CIN85-dependent manner. Finally, we demonstrate that SEPT9 negatively regulates EGFR degradation by preventing the association of the ubiquitin ligase Cbl with CIN85, resulting in reduced EGFR ubiquitylation. Taken together, these data provide a mechanistic explanation of how SEPT9, though acting exclusively at the plasma membrane, impairs the sorting of EGFRs into the degradative pathway.
authors.affiliation: Leibniz-Institut für Molekulare Pharmakologie (FMP), Robert-Rössle-Straße 10, 13125 Berlin, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Diesenberg
authors.affiliation: Leibniz-Institut für Molekulare Pharmakologie (FMP), Robert-Rössle-Straße 10, 13125 Berlin, Germany.
authors.forename: Monika
authors.initials: M
authors.lastname: Beerbaum
authors.affiliation: Leibniz-Institut für Molekulare Pharmakologie (FMP), Robert-Rössle-Straße 10, 13125 Berlin, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Fink
authors.affiliation: Leibniz-Institut für Molekulare Pharmakologie (FMP), Robert-Rössle-Straße 10, 13125 Berlin, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Schmieder
authors.affiliation: Leibniz-Institut für Molekulare Pharmakologie (FMP), Robert-Rössle-Straße 10, 13125 Berlin, Germany krauss@fmp-berlin.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Krauss
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D020816:Amino Acid Motifs / Q000235:genetics; D002462:Cell Membrane / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D053858:Metabolic Networks and Pathways; D011485:Protein Binding; D059748:Proteolysis; D034741:RNA, Small Interfering; D058112:Septins / Q000235:genetics / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D034741:RNA, Small Interfering; C433810:SH3KBP1 protein, human; D025801:Ubiquitin; C512478:EGFR protein, human; D066246:ErbB Receptors; C474315:SEPTIN9 protein, human; D058112:Septins
keywords: CIN85; EGFR; SEPT9; Sorting; Ubiquitylation