title: Tubedown regulation of retinal endothelial permeability signaling pathways.
abstract: Tubedown (Tbdn; Naa15), a subunit of the N-terminal acetyltransferase NatA, complexes with the c-Src substrate Cortactin and supports adult retinal homeostasis through regulation of vascular permeability. Here we investigate the role of Tbdn expression on signaling components of retinal endothelial permeability to understand how Tbdn regulates the vasculature and supports retinal homeostasis. Tbdn knockdown-induced hyperpermeability to Albumin in retinal endothelial cells was associated with an increase in the levels of activation of the Src family kinases (SFK) c-Src, Fyn and Lyn and phospho-Cortactin (Tyr421). The knockdown of Cortactin expression reduced Tbdn knockdown-induced permeability to Albumin and the levels of activated SFK. Inhibition of SFK in retinal endothelial cells decreased Tbdn knockdown-induced permeability to Albumin and phospho-Cortactin (Tyr421) levels. Retinal lesions of endothelial-specific Tbdn knockdown mice, with tissue thickening, fibrovascular growth, and hyperpermeable vessels displayed an increase in the levels of activated c-Src. Moreover, the retinal lesions of patients with proliferative diabetic retinopathy (PDR) associated with a loss of Tbdn expression and hyperpermeability to Albumin displayed increased levels of activated SFK in retinal blood vessels. Taken together, these results implicate Tbdn as an important regulator of retinal endothelial permeability and homeostasis by modulating a signaling pathway involving c-Src and Cortactin.
authors.affiliation: Division of BioMedical Sciences, Department of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland and Labrador, Canada A1B 3V6.
authors.forename: Nhu
authors.initials: N
authors.lastname: Ho
authors.affiliation: Division of BioMedical Sciences, Department of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland and Labrador, Canada A1B 3V6.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Gendron
authors.affiliation: Division of BioMedical Sciences, Department of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland and Labrador, Canada A1B 3V6.
authors.forename: Kindra
authors.initials: K
authors.lastname: Grozinger
authors.affiliation: Division of BioMedical Sciences, Department of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland and Labrador, Canada A1B 3V6.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Whelan
authors.affiliation: Division of BioMedical Sciences, Department of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland and Labrador, Canada A1B 3V6.
authors.forename: Emily Anne
authors.initials: EA
authors.lastname: Hicks
authors.affiliation: Division of BioMedical Sciences, Department of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland and Labrador, Canada A1B 3V6.
authors.forename: Bimal
authors.initials: B
authors.lastname: Tennakoon
authors.affiliation: Division of BioMedical Sciences, Department of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland and Labrador, Canada A1B 3V6.
authors.forename: Danielle
authors.initials: D
authors.lastname: Gardiner
authors.affiliation: Smith-Kettlewell Eye Research Institute, San Francisco, CA 94115, USA.
authors.forename: William V
authors.initials: WV
authors.lastname: Good
authors.affiliation: Division of BioMedical Sciences, Department of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland and Labrador, Canada A1B 3V6 hparadis@mun.ca.
authors.forename: Hélène
authors.initials: H
authors.lastname: Paradis
keywords: Cortactin; Endothelium; Permeability; Retina; Signaling; Tubedown; c-Src