title: Processing of CD109 by furin and its role in the regulation of TGF-beta signaling.
abstract: CD109 is a glycosylphosphatidylinositol (GPI)-anchored glycoprotein, whose expression is upregulated in squamous cell carcinomas of the lung, esophagus, uterus and oral cavity. CD109 negatively regulates transforming growth factor (TGF)-beta signaling in keratinocytes by directly modulating receptor activity. In this study, we further characterized CD109 regulation of TGF-beta signaling and cell proliferation. We found that CD109 is produced as a 205 kDa glycoprotein, which is then processed in the Golgi apparatus into 180 kDa and 25 kDa proteins by furin (furinase). 180 kDa CD109 associated with GPI-anchored 25 kDa CD109 on the cell surface and was also secreted into the culture medium. To investigate whether furinase cleavage of CD109 is necessary for its biological activity, we mutated arginine 1273 in the CD109 furinase cleavage motif (amino acid 1270-RRRR-1273) to serine (R1273S). Interestingly, CD109 R1273S neither significantly impaired TGF-beta signaling nor affected TGF-beta-mediated suppression of cell growth, although it was expressed on the cell surface as a 205 kDa protein. Consistent with this finding, the 180 kDa and 25 kDa CD109 complex, but not CD109 R1273S, associated with the type I TGF-beta receptor. These findings indicate that processing of CD109 into 180 kDa and 25 kDa proteins by furin, followed by complex formation with the type I TGF-beta receptor is required for the regulation of TGF-beta signaling in cancer cells and keratinocytes.
authors.affiliation: Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Hagiwara
authors.forename: Y
authors.initials: Y
authors.lastname: Murakumo
authors.forename: S
authors.initials: S
authors.lastname: Mii
authors.forename: T
authors.initials: T
authors.lastname: Shigetomi
authors.forename: N
authors.initials: N
authors.lastname: Yamamoto
authors.forename: H
authors.initials: H
authors.lastname: Furue
authors.forename: M
authors.initials: M
authors.lastname: Ueda
authors.forename: M
authors.initials: M
authors.lastname: Takahashi
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology; D015703:Antigens, CD / Q000096:biosynthesis / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D049109:Cell Proliferation; D003470:Culture Media / Q000378:metabolism; D000939:Epitopes / Q000276:immunology; D045683:Furin / Q000378:metabolism*; D058851:GPI-Linked Proteins; D006023:Glycoproteins / Q000096:biosynthesis / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D006031:Glycosylation; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D008970:Molecular Weight; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D009369:Neoplasms / Q000473:pathology; D021381:Protein Transport; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D012995:Solubility; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D000906:Antibodies; D015703:Antigens, CD; C120523:CD109 protein, human; D003470:Culture Media; D000939:Epitopes; D058851:GPI-Linked Proteins; D006023:Glycoproteins; D009363:Neoplasm Proteins; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D045683:Furin