title: Regulation of Sec16 levels and dynamics links proliferation and secretion.
abstract: We currently lack a broader mechanistic understanding of the integration of the early secretory pathway with other homeostatic processes such as cell growth. Here, we explore the possibility that Sec16A, a major constituent of endoplasmic reticulum exit sites (ERES), acts as an integrator of growth factor signaling. Surprisingly, we find that Sec16A is a short-lived protein that is regulated by growth factors in a manner dependent on Egr family transcription factors. We hypothesize that Sec16A acts as a central node in a coherent feed-forward loop that detects persistent growth factor stimuli to increase ERES number. Consistent with this notion, Sec16A is also regulated by short-term growth factor treatment that leads to increased turnover of Sec16A at ERES. Finally, we demonstrate that Sec16A depletion reduces proliferation, whereas its overexpression increases proliferation. Together with our finding that growth factors regulate Sec16A levels and its dynamics on ERES, we propose that this protein acts as an integrator linking growth factor signaling and secretion. This provides a mechanistic basis for the previously proposed link between secretion and proliferation.
authors.affiliation: Biotechnology Institute Thurgau (BITg) at the University of Konstanz, Unterseestrasse 47, CH-8280 Kreuzlingen, Switzerland University of Konstanz, Universitätsstrasse 10, Konstanz 78464, Germany.
authors.forename: Kerstin D
authors.initials: KD
authors.lastname: Tillmann
authors.affiliation: Biotechnology Institute Thurgau (BITg) at the University of Konstanz, Unterseestrasse 47, CH-8280 Kreuzlingen, Switzerland.
authors.forename: Veronika
authors.initials: V
authors.lastname: Reiterer
authors.affiliation: Biotechnology Institute Thurgau (BITg) at the University of Konstanz, Unterseestrasse 47, CH-8280 Kreuzlingen, Switzerland University of Konstanz, Universitätsstrasse 10, Konstanz 78464, Germany.
authors.forename: Francesco
authors.initials: F
authors.lastname: Baschieri
authors.affiliation: Experimental Physics I, University of Bayreuth, Bayreuth 95440, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Hoffmann
authors.affiliation: Biotechnology Institute Thurgau (BITg) at the University of Konstanz, Unterseestrasse 47, CH-8280 Kreuzlingen, Switzerland University of Konstanz, Universitätsstrasse 10, Konstanz 78464, Germany.
authors.forename: Valentina
authors.initials: V
authors.lastname: Millarte
authors.affiliation: Biotechnology Institute Thurgau (BITg) at the University of Konstanz, Unterseestrasse 47, CH-8280 Kreuzlingen, Switzerland.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Hauser
authors.affiliation: Blavatnik School of Computer Science, Tel Aviv University, Tel-Aviv 69978, Israel.
authors.forename: Arnon
authors.initials: A
authors.lastname: Mazza
authors.affiliation: Blavatnik School of Computer Science, Tel Aviv University, Tel-Aviv 69978, Israel.
authors.forename: Nir
authors.initials: N
authors.lastname: Atias
authors.affiliation: Biotechnology Institute Thurgau (BITg) at the University of Konstanz, Unterseestrasse 47, CH-8280 Kreuzlingen, Switzerland.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Legler
authors.affiliation: Blavatnik School of Computer Science, Tel Aviv University, Tel-Aviv 69978, Israel.
authors.forename: Roded
authors.initials: R
authors.lastname: Sharan
authors.affiliation: Experimental Physics I, University of Bayreuth, Bayreuth 95440, Germany matthias.weiss@uni-bayreuth.de hesso.farhan@uni-konstanz.de.
authors.forename: Matthias
authors.initials: M
authors.lastname: Weiss
authors.affiliation: Biotechnology Institute Thurgau (BITg) at the University of Konstanz, Unterseestrasse 47, CH-8280 Kreuzlingen, Switzerland University of Konstanz, Universitätsstrasse 10, Konstanz 78464, Germany matthias.weiss@uni-bayreuth.de hesso.farhan@uni-konstanz.de.
authors.forename: Hesso
authors.initials: H
authors.lastname: Farhan
mesh_terms: D022181:COP-Coated Vesicles / Q000378:metabolism*; D002460:Cell Line; D049109:Cell Proliferation / Q000235:genetics / Q000502:physiology*; D051766:Early Growth Response Protein 1 / Q000235:genetics; D051776:Early Growth Response Protein 3 / Q000235:genetics; D051765:Early Growth Response Transcription Factors / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006056:Golgi Apparatus / Q000378:metabolism; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics; D054778:NM23 Nucleoside Diphosphate Kinases / Q000235:genetics; D009701:Nucleoside-Diphosphate Kinase / Q000235:genetics; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics; D055571:Secretory Pathway / Q000502:physiology*; D015398:Signal Transduction; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C497325:EGR1 protein, human; C079945:EGR3 protein, human; D051766:Early Growth Response Protein 1; D051765:Early Growth Response Transcription Factors; D054778:NM23 Nucleoside Diphosphate Kinases; C517948:NME5 protein, human; C517555:SEC16A protein, human; D033921:Vesicular Transport Proteins; D051776:Early Growth Response Protein 3; D017853:Phosphotransferases (Alcohol Group Acceptor); C020077:1-phosphatidylinositol-4-phosphate 5-kinase; C000606139:NME6 protein, human; C000595354:NME7 protein, human; D009701:Nucleoside-Diphosphate Kinase; C493083:SAR1A protein, human; D020559:Monomeric GTP-Binding Proteins
keywords: ER exit sites; Sec16; Signaling