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Identification of CD109 as part of the TGF‐β receptor system in human keratinocytes

2006; Wiley; Volume: 20; Issue: 9 Linguagem: Inglês

10.1096/fj.05-5229fje

1530-6860

Kenneth W. Finnson, Betty Y. Tam, Kai Liu, Anne Marcoux, Patricia Lepage, Stéphane Roy, Albane A. Bizet, Anie Philip, Kenneth W. Finnson, Betty Y. Tam, Kai Liu, Anne Marcoux, Patricia Lepage, Stéphane Roy, Albane A. Bizet, Anie Philip,

Cancer-related gene regulation

We have previously reported that keratinocytes defective in glycosylphosphatidylinositol (GPI)-anchor biosynthesis display enhanced TGF-beta responses. These studies implicated the involvement of a 150 kDa GPI-anchored TGF-beta1 binding protein, r150, in modulating TGF-beta signaling. Here, we sought to determine the molecular identity of r150 by affinity purification and microsequencing. Our results identify r150 as CD109, a novel member of the alpha2-macroglobulin (alpha2M)/complement superfamily, whose function has remained obscure. In addition, we have identified a novel CD109 isoform that occurs in the human placenta but not keratinocytes. Biochemical studies show that r150 contains an internal thioester bond, a defining feature of the alpha2M/complement family. Loss and gain of function studies demonstrate that CD109 is a component of the TGF-beta receptor system, and a negative modulator of TGF-beta responses in keratinocytes, as implicated for r150. Our data suggest that CD109 can inhibit TGF-beta signaling independently of ligand sequestration and may exert its effect on TGF-beta signaling by direct modulation of receptor activity. Together, our results linking CD109 function to regulation of TGF-beta signaling suggest that CD109 plays a unique role in the regulation of isoform-specific TGF-beta signaling in keratinocytes.