title: Focal Adhesion Kinase-mediated Phosphorylation of Beclin1 Protein Suppresses Cardiomyocyte Autophagy and Initiates Hypertrophic Growth.
abstract: Autophagy is an evolutionarily conserved intracellular degradation/recycling system that is essential for cellular homeostasis but is dysregulated in a number of diseases, including myocardial hypertrophy. Although it is clear that limiting or accelerating autophagic flux can result in pathological cardiac remodeling, the physiological signaling pathways that fine-tune cardiac autophagy are poorly understood. Herein, we demonstrated that stimulation of cardiomyocytes with phenylephrine (PE), a well known hypertrophic agonist, suppresses autophagy and that activation of focal adhesion kinase (FAK) is necessary for PE-stimulated autophagy suppression and subsequent initiation of hypertrophic growth. Mechanistically, we showed that FAK phosphorylates Beclin1, a core autophagy protein, on Tyr-233 and that this post-translational modification limits Beclin1 association with Atg14L and reduces Beclin1-dependent autophagosome formation. Remarkably, although ectopic expression of wild-type Beclin1 promoted cardiomyocyte atrophy, expression of a Y233E phosphomimetic variant of Beclin1 failed to affect cardiomyocyte size. Moreover, genetic depletion of Beclin1 attenuated PE-mediated/FAK-dependent initiation of myocyte hypertrophyin vivoCollectively, these findings identify FAK as a novel negative regulator of Beclin1-mediated autophagy and indicate that this pathway can facilitate the promotion of compensatory hypertrophic growth. This novel mechanism to limit Beclin1 activity has important implications for treating a variety of pathologies associated with altered autophagic flux.
authors.affiliation: From the Department of Pathology.
authors.forename: Zhaokang
authors.initials: Z
authors.lastname: Cheng
authors.affiliation: From the Department of Pathology.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhu
authors.affiliation: From the Department of Pathology.
authors.forename: Rachel
authors.initials: R
authors.lastname: Dee
authors.affiliation: From the Department of Pathology.
authors.forename: Zachary
authors.initials: Z
authors.lastname: Opheim
authors.affiliation: From the Department of Pathology.|McAllister Heart Institute, and.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Mack
authors.affiliation: Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, North Carolina 27599.
authors.forename: Douglas M
authors.initials: DM
authors.lastname: Cyr
authors.affiliation: From the Department of Pathology, jmt3x@med.unc.edu.|McAllister Heart Institute, and.
authors.forename: Joan M
authors.initials: JM
authors.lastname: Taylor
mesh_terms: D000818:Animals; D001343:Autophagy; D000071186:Beclin-1 / Q000235:genetics / Q000378:metabolism*; D006332:Cardiomegaly / Q000473:pathology*; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000473:pathology*; D010766:Phosphorylation; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000071186:Beclin-1; C115010:Becn1 protein, mouse; D011942:Receptors, Adrenergic, alpha; D051416:Focal Adhesion Protein-Tyrosine Kinases
keywords: Beclin-1 (BECN1); PTK2 protein tyrosine kinase 2 (PTK2) (focal adhesion kinase) (FAK); atrophy; autophagy; cardiac hypertrophy; muscle atrophy