title: Interaction between Her2 and Beclin-1 proteins underlies a new mechanism of reciprocal regulation.
abstract: Beclin-1 is a key regulator of autophagy that functions in the context of two phase-specific complexes in the initiation and maturation of autophagosomes. Its known interacting proteins include autophagy effectors, Bcl-2 family members, and organelle membrane anchor proteins. Here we report a newly identified interaction between Beclin-1 and the protein tyrosine kinase receptor Her2. We demonstrate that in Her2-expressing breast carcinoma cells that do not succumb to lapatinib, this Her1/2 inhibitor disrupts the cell surface interaction between Her2 and Beclin-1. The data suggest that the ensuing autophagic response is correlatively associated with the release of Beclin-1 from its complex with Her2 and with the subsequent increase in cytosolic Beclin-1. Upon its interaction with Her2, Beclin-1 up-regulates the phosphorylation levels of Her2 and Akt. The Beclin-1 evolutionarily conserved domain is required both for the interaction of Beclin-1 with Her2 and for the increased Her2 and Akt phosphorylation. These findings shed new light on mechanisms involved in lapatinib-mediated autophagy in Her2-expressing breast carcinoma cell lines and in Beclin-1 signaling in these cells.
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine and the University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15213, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Han
authors.forename: Wen
authors.initials: W
authors.lastname: Hou
authors.forename: Caisheng
authors.initials: C
authors.lastname: Lu
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Goldstein
authors.forename: Donna B
authors.initials: DB
authors.lastname: Stolz
authors.forename: Simon C
authors.initials: SC
authors.lastname: Watkins
authors.forename: Hannah
authors.initials: H
authors.lastname: Rabinowich
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D001343:Autophagy / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D000071186:Beclin-1; D045744:Cell Line, Tumor; D006801:Humans; D019169:Jurkat Cells; D000077341:Lapatinib; D061986:MCF-7 Cells; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D046529:Microscopy, Electron, Transmission; D010588:Phagosomes / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology; D034622:RNA Interference; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; D000077341:Lapatinib; D008565:Membrane Proteins; D051057:Proto-Oncogene Proteins c-akt; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C491997:BECN1 protein, human
keywords: Apoptosis; Autophagy; Beclin-1; Breast Cancer; Epidermal Growth Factor Receptor (EGFR); Her2; Lapatinib; Receptor Tyrosine Kinase