title: Neuregulin activates erbB2-dependent src/FAK signaling and cytoskeletal remodeling in isolated adult rat cardiac myocytes.
abstract: Cardiac myocyte erbB2 expression is required for maintenance of normal cardiac structure and function, though its role in cardiac cellular physiology is incompletely understood. We tested the hypothesis that erbB2 signaling modulates focal adhesion formation via activation of a src/FAK pathway using adult rat ventricular myocytes in primary culture. The erbB ligand neuregulin-1Beta (NRG-1Beta) induced phosphorylation of Src at Y416 and Y215, and FAK at Y861. Using antibody and pharmacological inhibitor strategies, we found that FAK activation was erbB2- and Src-dependent, but independent of PI3-kinase/Akt pathway. Furthermore, NRG-1Beta stimulated the formation of a multiprotein complex between erbB2, FAK, p130(CAS) and paxillin within 30 min, and induced lamellipodia with longitudinal elongation of the myocytes within days. The extension of lamellipodia resulted in restoration of cell-to-cell contact between isolated myocytes, allowing for synchronous beating. These effects of NRG-1Beta were prevented by a src inhibitor as well as an antibody to erbB2. These results suggest the potential role of NRG-1Beta/erbB2/Src/FAK signaling in the maintenance and repair of electrical and mechanical coupling in cardiomyocytes.
authors.affiliation: Center for Molecular Stress Response, Whitaker Cardiovascular Institute, Department of Medicine, Boston University Medical Center, MA 02118, USA.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Kuramochi
authors.forename: Xinxin
authors.initials: X
authors.lastname: Guo
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Sawyer
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism*; D006352:Heart Ventricles / Q000166:cytology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000201:enzymology*; D020890:Neuregulin-1 / Q000378:metabolism* / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects / Q000502:physiology; D051381:Rats; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D016276:Ventricular Function; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D051416:Focal Adhesion Protein-Tyrosine Kinases; D020890:Neuregulin-1; D018719:Erb-b2 Receptor Tyrosine Kinases; D019061:src-Family Kinases; C117467:neuregulin beta