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Identification of CD109 as part of the TGF-ß receptor system in human keratinocytes

Kenneth W. Finnson^*,1, Betty Y. Y. Tam^*,1,2, Kai Liu^*,3, Anne Marcoux^*, Pierre Lepage, Stephane Roy, Albane A. Bizet^* and Anie Philip^*,4

^* Department of Surgery, McGill University, Montreal, Quebec, Canada;

McGill University and Genome Quebec Innovation Center, Montreal, Quebec, Canada; and

Département de Stomatologie, Université de Montréal, Quebec, Canada

⁴Correspondence: McGill University, Montreal General Hospital, 1650 Cedar Ave., Rm. C9–177, Montreal, Quebec H3G 1A4, Canada. E-mail: anie.philip{at}mcgill.ca

ABSTRACT

We have previously reported that keratinocytes defective in glycosylphosphatidylinositol (GPI)-anchor biosynthesis display enhanced TGF-ß responses. These studies implicated the involvement of a 150 kDa GPI-anchored TGF-ß1 binding protein, r150, in modulating TGF-ß 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 2-macroglobulin (2M)/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 2M/complement family. Loss and gain of function studies demonstrate that CD109 is a component of the TGF-ß receptor system, and a negative modulator of TGF-ß responses in keratinocytes, as implicated for r150. Our data suggest that CD109 can inhibit TGF-ß signaling independently of ligand sequestration and may exert its effect on TGF-ß signaling by direct modulation of receptor activity. Together, our results linking CD109 function to regulation of TGF-ß signaling suggest that CD109 plays a unique role in the regulation of isoform-specific TGF-ß signaling in keratinocytes.—Finnson, K. W., Tam, B. Y. Y., Liu, K., Marcoux, A., Lepage, P., Roy, S., Bizet, A. A., Philip, A. Identification of CD109 as a TGF-ß1 accessory receptor in human keratinocytes.