ISSN:
1524-475X
Source:
Blackwell Publishing Journal Backfiles 1879-2005
Topics:
Medicine
Notes:
The potential of TGF-β isoforms to regulate wound healing and scarring is well documented in animal models. Since TGF-β action is likely to be regulated at the level of its cell surface receptors, we analyzed TGF-β receptor profiles and regulation of TGF-β signaling in human keratinocytes. We identified a novel cell surface TGF-β1 binding protein of 150 kDa (r150) on human keratinocytes that interacts with the TGF-β signaling receptors. Further characterization of r150 demonstrated that it is a GPI-anchored protein, that it can be released from the cell surface by an endogenous phospholipase C, and that the released form can bind to TGF-β1. Recent cloning of r150 revealed it to be a novel protein of 1428 amino acids. Our objective was to determine the functional significance of r150 in regulating TGF-β responses in keratinocytes.Affinity labeling of keratinocytes overexpressing r150 cDNA and immunoprecipitation stud-ies using anti-r150 antibodies show that the cloned cDNA represents r150. Importantly, over expression of r150 results in inhibition of TGF-β1-induced Smad 2 and Smad 3 phosphorylation, gene transcriptional activity, and keratinocyte migration. In contrast, loss of r150 function using antisense morpholino oligos of r150 leads to enhanced Smad 2 and Smad 3 phosphorylation, gene transcriptional activity and proliferation of keratinocytes. In summary, our results demonstrate that r150 is a potent inhibitor of TGF-β signaling in keratinocytes, and that it may have potential therapeutic value in modulating TGF-β action in human diseases where TGF-β plays a pathophysiological role. As such, r150 may be of use in reducing hypertrophic scarring, and an r150 antagonist may promote wound healing.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1111/j.1067-1927.2004.0abstractaf.x
