title: Modulation of type II TGF-β receptor degradation by integrin-linked kinase.
abstract: Cutaneous responses to injury, infection, and tumor formation involve the activation of resident dermal fibroblasts and subsequent transition to myofibroblasts. The key for induction of myofibroblast differentiation is the activation of transforming growth factor-β (TGF-β) receptors and stimulation of integrins and their associated proteins, including integrin-linked kinase (ILK). Cross-talk processes between TGF-β and ILK are crucial for myofibroblast formation, as ILK-deficient dermal fibroblasts exhibit impaired responses to TGF-β receptor stimulation. We now show that ILK associates with type II TGF-β receptors (TβRII) in ligand- and receptor kinase activity-independent manners. In cells with targeted Ilk gene inactivation, cellular levels of TβRII are decreased, through mechanisms that involve enhanced ubiquitination and proteasomal degradation. Partitioning of TGF-β receptors into membrane has been linked to proteasome-dependent receptor degradation. We found that interfering with membrane raft formation in ILK-deficient cells restored TβRII levels and signaling. These observations support a model whereby ILK functions in fibroblasts to direct TβRII away from degradative pathways during their differentiation into myofibroblasts.
authors.affiliation: Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada; Children's Health Research Institute, Lawson Health Research Institute, University of Western Ontario, London, Ontario, Canada.
authors.forename: Linda
authors.initials: L
authors.lastname: Vi
authors.affiliation: Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada; Children's Health Research Institute, Lawson Health Research Institute, University of Western Ontario, London, Ontario, Canada; These authors contributed equally to this work.
authors.forename: Stellar
authors.initials: S
authors.lastname: Boo
authors.affiliation: Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada; Children's Health Research Institute, Lawson Health Research Institute, University of Western Ontario, London, Ontario, Canada.
authors.forename: Samar
authors.initials: S
authors.lastname: Sayedyahossein
authors.affiliation: Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada; Children's Health Research Institute, Lawson Health Research Institute, University of Western Ontario, London, Ontario, Canada.
authors.forename: Randeep K
authors.initials: RK
authors.lastname: Singh
authors.affiliation: Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada.
authors.forename: Sarah
authors.initials: S
authors.lastname: McLean
authors.affiliation: Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada.
authors.forename: Gianni M
authors.initials: GM
authors.lastname: Di Guglielmo
authors.affiliation: Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada; Children's Health Research Institute, Lawson Health Research Institute, University of Western Ontario, London, Ontario, Canada. Electronic address: ldagnino@uwo.ca.
authors.forename: Lina
authors.initials: L
authors.lastname: Dagnino
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D023421:Models, Animal; D058628:Myofibroblasts / Q000378:metabolism / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D012867:Skin / Q000378:metabolism* / Q000473:pathology; D000099200:Scaffold Protein ILK
chemical_list: D046988:Proteasome Endopeptidase Complex; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta; D000099200:Scaffold Protein ILK