title: Beclin 1 regulates growth factor receptor signaling in breast cancer.
abstract: Beclin 1 is a haploinsufficient tumor suppressor that is decreased in many human tumors. The function of beclin 1 in cancer has been attributed primarily to its role in the degradative process of macroautophagy. However, beclin 1 is a core component of the vacuolar protein sorting 34 (Vps34)/class III phosphatidylinositoI-3 kinase (PI3KC3) and Vps15/p150 complex that regulates multiple membrane-trafficking events. In the current study, we describe an alternative mechanism of action for beclin 1 in breast cancer involving its control of growth factor receptor signaling. We identify a specific stage of early endosome maturation that is regulated by beclin 1, the transition of APPL1-containing phosphatidyIinositol 3-phosphate-negative (PI3P(-)) endosomes to PI3P(+) endosomes. Beclin 1 regulates PI3P production in response to growth factor stimulation to control the residency time of growth factor receptors in the PI3P(-)/APPL(+)-signaling-competent compartment. As a result, suppression of BECN1 sustains growth factor-stimulated AKT and ERK activation resulting in increased breast carcinoma cell invasion. In human breast tumors, beclin 1 expression is inversely correlated with AKT and ERK phosphorylation. Our data identify a novel role for beclin 1 in regulating growth factor signaling and reveal a mechanism by which loss of beclin 1 expression would enhance breast cancer progression.
authors: Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA, USA.
authors: R A
authors: RA
authors: Rohatgi
authors: Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA, USA.
authors: J
authors: J
authors: Janusis
authors: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
authors: D
authors: D
authors: Leonard
authors: Biomedical Imaging Group, University of Massachusetts Medical School, Worcester, MA, USA.
authors: K D
authors: KD
authors: Bellvé
authors: Biomedical Imaging Group, University of Massachusetts Medical School, Worcester, MA, USA.
authors: K E
authors: KE
authors: Fogarty
authors: Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA, USA.
authors: E H
authors: EH
authors: Baehrecke
authors: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
authors: S
authors: S
authors: Corvera
authors: Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA, USA.
authors: L M
authors: LM
authors: Shaw
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000502:physiology*; D000071187:Autophagy-Related Protein 5; D000071186:Beclin-1; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D058546:Class III Phosphatidylinositol 3-Kinases / Q000502:physiology; D004815:Epidermal Growth Factor / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D061986:MCF-7 Cells; D008565:Membrane Proteins / Q000502:physiology*; D008869:Microtubule-Associated Proteins / Q000502:physiology; D009687:Nuclear Proteins; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017978:Receptors, Growth Factor / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors
chemical_list: C464801:APPL1 protein, human; C502778:ATG5 protein, human; D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D000071187:Autophagy-Related Protein 5; C491997:BECN1 protein, human; D000071186:Beclin-1; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D009687:Nuclear Proteins; C503859:PI3KCA protein, human; D017978:Receptors, Growth Factor; D014157:Transcription Factors; D004815:Epidermal Growth Factor; D007334:Insulin-Like Growth Factor I; D058546:Class III Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases
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