title: Overexpression of CD109 in the Epidermis Differentially Regulates ALK1 Versus ALK5 Signaling and Modulates Extracellular Matrix Synthesis in the Skin.
abstract: Transforming growth factor-β (TGF-β) is a multifunctional growth factor involved in many physiological processes including wound healing and inflammation. Excessive TGF-β signaling in the skin has been implicated in fibrotic skin disorders such as keloids and scleroderma. We previously identified CD109 as a TGF-β co-receptor and inhibitor of TGF-β signaling and have shown that transgenic mice overexpressing CD109 in the epidermis display decreased scarring. In certain cell types, in addition to the canonical type I receptor, ALK5, which activates Smad2/3, TGF-β can signal through another type I receptor, ALK1, which activates Smad1/5. Here we demonstrate that ALK1 is expressed and co-localizes with CD109 in mouse keratinocytes and that mice overexpressing CD109 in the epidermis display enhanced ALK1-Smad1/5 signaling but decreased ALK5-Smad2/3 signaling, TGF-β expression, and extracellular matrix production in the skin when compared with wild-type littermates. Furthermore, treatment with conditioned media from isolated keratinocytes or epidermal explants from CD109 transgenic mouse skin leads to a decrease in extracellular matrix production in mouse skin fibroblasts. Taken together, our findings suggest that CD109 differentially regulates TGF-β-induced ALK1-Smad1/5 versus ALK5-Smad2/3 pathways, leading to decreased extracellular matrix production in the skin and that epidermal CD109 expression regulates dermal function through a paracrine mechanism.
authors.affiliation: Division of Plastic Surgery, Department of Surgery, McGill University, Montreal, Quebec, Canada.
authors.forename: Joshua
authors.initials: J
authors.lastname: Vorstenbosch
authors.affiliation: Division of Plastic Surgery, Department of Surgery, McGill University, Montreal, Quebec, Canada.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Nguyen
authors.affiliation: Division of Plastic Surgery, Department of Surgery, McGill University, Montreal, Quebec, Canada.
authors.forename: Shufeng
authors.initials: S
authors.lastname: Zhou
authors.affiliation: Faculty of Dentistry, McGill University, McGill University, Montreal, Canada.
authors.forename: You Jung
authors.initials: YJ
authors.lastname: Seo
authors.affiliation: Division of Plastic Surgery, Department of Surgery, McGill University, Montreal, Quebec, Canada.
authors.forename: Aya
authors.initials: A
authors.lastname: Siblini
authors.affiliation: Division of Plastic Surgery, Department of Surgery, McGill University, Montreal, Quebec, Canada.
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Finnson
authors.affiliation: Division of Plastic Surgery, Department of Surgery, McGill University, Montreal, Quebec, Canada.
authors.forename: Albane A
authors.initials: AA
authors.lastname: Bizet
authors.affiliation: Faculty of Dentistry, McGill University, McGill University, Montreal, Canada.
authors.forename: Simon D
authors.initials: SD
authors.lastname: Tran
authors.affiliation: Division of Plastic Surgery, Department of Surgery, McGill University, Montreal, Quebec, Canada. Electronic address: anie.philip@mcgill.ca.
authors.forename: Anie
authors.initials: A
authors.lastname: Philip
mesh_terms: D030201:Activin Receptors, Type I / Q000378:metabolism*; D030301:Activin Receptors, Type II; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D004817:Epidermis / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology; D051379:Mice; D008822:Mice, Transgenic; D009363:Neoplasm Proteins / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D015398:Signal Transduction; D012867:Skin / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D015703:Antigens, CD; C548464:CD109 protein, mouse; D009363:Neoplasm Proteins; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D030201:Activin Receptors, Type I; D030301:Activin Receptors, Type II; C498931:Acvrl1 protein, mouse; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625842:Tgfbr1 protein, mouse