Transforming growth factor-beta (TGF-beta) signaling is involved in a wide array of cellular responses in both physiological and pathological conditions. Dysregulation of TGF-beta action can lead to impaired tissue homeostasis and several developmental defects. Mechanisms regulating TGF-beta signal transduction include modulation of TGF-beta signaling receptor activity by accessory receptors. Our group has recently identified a GPI-anchored TGF-beta1 binding protein, r150, and has shown that it is implicated in the regulation of TGF-beta signaling in keratinocytes. Recent molecular cloning of r150 in our laboratory shows that it represents CD109, a novel member of the alpha2-macroglobulin/complement (AMCOM) gene family. / We provided evidence showing that r150 contains an intact internal thioester bond, which is one of the defining characteristics of almost all members of the alpha2M/complement family, including CD109. Using affinity labeling, immunoprecipitation and Western blot analysis, we demonstrated that r150 binds TGF-beta1 with high affinity and associates with the TGF-beta receptors indicating that it is a component of the TGF-beta signaling complex. In addition, overexpression of r150 resulted in a significant decrease in TGF-beta-induced wound closure and TGF-beta-mediated growth inhibition. In contrast, blocking the expression of r150 by an antisense approach enhanced the above responses. Importantly, immunohistochemical analysis showed that r150 expression is markedly decreased in psoriatic lesions when compared to adjacent normal skin. / In summary, our results demonstrated that r150 is a negative modulator of TGF-beta responses in keratinocytes, and that it might be a potential marker or molecular target for therapeutic intervention in modulating TGF-beta action in human diseases where TGF-beta plays a pathophysiological role.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.84058 |
| Date | January 2005 |
| Creators | Marcoux, Anne, 1978- |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Master of Science (Division of Surgical Research.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 002262016, proquestno: AAIMR22750, Theses scanned by UMI/ProQuest. |
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