title: Biomechanical insult switches PEA-15 activity to uncouple its anti-apoptotic function and promote erk mediated tissue remodeling.
abstract: Biomechanical insult contributes to many chronic pathological processes, yet the resulting influences on signal transduction mechanisms are poorly understood. The retina presents an excellent mechanotransduction model, as mechanical strain on sensitive astrocytes of the optic nerve head (ONH) is intimately linked to chronic tissue remodeling and excavation by matrix metalloproteinases (MMPs), and apoptotic cell death. However, the mechanism by which these effects are induced by biomechanical strain is unclear. We previously identified the small adapter protein, PEA-15 (phosphoprotein enriched in astrocytes), through proteomic analyses of human ONH astrocytes subjected to pathologically relevant biomechanical insult. Under resting conditions PEA-15 is regulated through phosphorylation of two key serine residues to inhibit extrinsic apoptosis and ERK1/2 signaling. However, we surprisingly observed that biomechanical insult dramatically switches PEA-15 phosphorylation and function to uncouple its anti-apoptotic activity, and promote ERK1/2-dependent MMP-2 and MMP-9 secretion. These results reveal a novel cell autonomous mechanism by which biomechanical strain rapidly modifies this signaling pathway to generate altered tissue injury responses.
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada M5S 2J7; Vision Science Research Program, Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, ON, Canada M5S 2J7; Department of Vision Science, Toronto Western Research Institute University Health Network, Toronto, ON, Canada, M5G 2C4.
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Exler
authors.affiliation: Department of Vision Science, Toronto Western Research Institute University Health Network, Toronto, ON, Canada, M5G 2C4.
authors.forename: Xiaoxin
authors.initials: X
authors.lastname: Guo
authors.affiliation: Department of Vision Science, Toronto Western Research Institute University Health Network, Toronto, ON, Canada, M5G 2C4.
authors.forename: Darren
authors.initials: D
authors.lastname: Chan
authors.affiliation: School of Optometry, University of California Berkeley, United States.
authors.forename: Izhar
authors.initials: I
authors.lastname: Livne-Bar
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada M5S 2J7; Vision Science Research Program, Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, ON, Canada M5S 2J7; Department of Vision Science, Toronto Western Research Institute University Health Network, Toronto, ON, Canada, M5G 2C4.
authors.forename: Nevena
authors.initials: N
authors.lastname: Vicic
authors.affiliation: Vision Science Research Program, Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, ON, Canada M5S 2J7; Department of Vision Science, Toronto Western Research Institute University Health Network, Toronto, ON, Canada, M5G 2C4; School of Optometry, University of California Berkeley, United States.
authors.forename: John G
authors.initials: JG
authors.lastname: Flanagan
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada M5S 2J7; Vision Science Research Program, Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, ON, Canada M5S 2J7; Department of Vision Science, Toronto Western Research Institute University Health Network, Toronto, ON, Canada, M5G 2C4. Electronic address: jsivak@uhnres.utoronto.ca.
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Sivak
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D001253:Astrocytes / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology*; D040542:Mechanotransduction, Cellular / Q000502:physiology*; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D040901:Proteomics; D017208:Rats, Wistar; D012160:Retina / Q000166:cytology*
chemical_list: D051017:Apoptosis Regulatory Proteins; C490443:Pea15 protein, rat; D010750:Phosphoproteins; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Apoptosis; Astrocytes; Biomechanics; ERK; MMPs; PEA-15