Interaction between Her2 and Beclin-1 Proteins Underlies a New Mechanism of Reciprocal Regulation

• Published in: The Journal of biological chemistry Vol. 288; no. 28; pp. 20315 - 20325
• Main Authors: Han, Jie, Hou, Wen, Lu, Caisheng, Goldstein, Leslie A., Stolz, Donna B., Watkins, Simon C., Rabinowich, Hannah
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 12.07.2013; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Apoptosis - genetics; Apoptosis - physiology; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; Autophagy; Autophagy - drug effects; Autophagy - genetics; Autophagy - physiology; Beclin-1; Breast Cancer; Cell Line, Tumor; Epidermal Growth Factor Receptor (EGFR); Her2; Humans; Jurkat Cells; Lapatinib; MCF-7 Cells; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Microscopy, Electron, Transmission; Phagosomes - drug effects; Phagosomes - metabolism; Phagosomes - ultrastructure; Phosphorylation - drug effects; Protein Binding - drug effects; Proto-Oncogene Proteins c-akt - metabolism; Quinazolines - pharmacology; Receptor Tyrosine Kinase; Receptor, ErbB-2 - genetics; Receptor, ErbB-2 - metabolism; RNA Interference; Signal Transduction; Beclin-1; Epidermal Growth Factor Receptor (EGFR); Lapatinib; Autophagy; Breast Cancer; Apoptosis; Receptor Tyrosine Kinase; Her2
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M113.461350

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. Background: Beclin-1 is one of the essential autophagic proteins. Results: This study identified a novel complex between breast carcinoma Her2 and Beclin-1 that is disrupted by lapatinib, a Her2-tyrosine kinase inhibitor. Conclusion: Lapatinib thwarts the reciprocal cross-regulation between Her2 and Beclin-1, impacting cellular autophagy and Her2 signaling. Significance: The findings elucidate a hitherto unknown association between lapatinib-induced autophagy and the disruption of Her2-Beclin-1 complex.