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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.
AuthorsJie Han, Wen Hou, Caisheng Lu, Leslie A Goldstein, Donna B Stolz, Simon C Watkins, Hannah Rabinowich
JournalThe Journal of biological chemistry (J Biol Chem) Vol. 288 Issue 28 Pg. 20315-25 (Jul 12 2013) ISSN: 1083-351X [Electronic] United States
PMID23703612 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
Chemical References
  • Antineoplastic Agents
  • Apoptosis Regulatory Proteins
  • BECN1 protein, human
  • Membrane Proteins
  • Quinazolines
  • lapatinib
  • Receptor, ErbB-2
  • Proto-Oncogene Proteins c-akt
Topics
  • Animals
  • Antineoplastic Agents (pharmacology)
  • Apoptosis (drug effects, genetics, physiology)
  • Apoptosis Regulatory Proteins (genetics, metabolism)
  • Autophagy (drug effects, genetics, physiology)
  • Cell Line, Tumor
  • Humans
  • Jurkat Cells
  • MCF-7 Cells
  • Membrane Proteins (genetics, metabolism)
  • Mice
  • Microscopy, Electron, Transmission
  • Phagosomes (drug effects, metabolism, ultrastructure)
  • Phosphorylation (drug effects)
  • Protein Binding (drug effects)
  • Proto-Oncogene Proteins c-akt (metabolism)
  • Quinazolines (pharmacology)
  • RNA Interference
  • Receptor, ErbB-2 (genetics, metabolism)

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