title: Ectodomain shedding of TβRIII is required for TβRIII-mediated suppression of TGF-β signaling and breast cancer migration and invasion.
abstract: The type III transforming growth factor β (TGF-β) receptor (TβRIII), also known as betaglycan, is the most abundantly expressed TGF-β receptor. TβRIII suppresses breast cancer progression by inhibiting migration, invasion, metastasis, and angiogenesis. TβRIII binds TGF-β ligands, with membrane-bound TβRIII presenting ligand to enhance TGF-β signaling. However, TβRIII can also undergo ectodomain shedding, releasing soluble TβRIII, which binds and sequesters ligand to inhibit downstream signaling. To investigate the relative contributions of soluble and membrane-bound TβRIII on TGF-β signaling and breast cancer biology, we defined TβRIII mutants with impaired (ΔShed-TβRIII) or enhanced ectodomain shedding (SS-TβRIII). Inhibiting ectodomain shedding of TβRIII increased TGF-β responsiveness and abrogated TβRIII's ability to inhibit breast cancer cell migration and invasion. Conversely, expressing SS-TβRIII, which increased soluble TβRIII production, decreased TGF-β signaling and increased TβRIII-mediated inhibition of breast cancer cell migration and invasion. Of importance, SS-TβRIII-mediated increases in soluble TβRIII production also reduced breast cancer metastasis in vivo. Taken together, these studies suggest that the ratio of soluble TβRIII to membrane-bound TβRIII is an important determinant for regulation of TβRIII- and TGF-β-mediated signaling and biology.
authors: Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27708.
authors: Jennifer L
authors: JL
authors: Elderbroom
authors: Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27708.
authors: Jennifer J
authors: JJ
authors: Huang
authors: Department of Medicine, Duke University, Durham, NC 27708.
authors: Catherine E
authors: CE
authors: Gatza
authors: Department of Medicine, Duke University, Durham, NC 27708.
authors: Jian
authors: J
authors: Chen
authors: Department of Medicine, Duke University, Durham, NC 27708.
authors: Tam
authors: T
authors: How
authors: Department of Medicine, Duke University, Durham, NC 27708.
authors: Mark
authors: M
authors: Starr
authors: Department of Medicine, Duke University, Durham, NC 27708.
authors: Andrew B
authors: AB
authors: Nixon
authors: Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27708Department of Medicine, Duke University, Durham, NC 27708 gerard.blobe@duke.edu.
authors: Gerard C
authors: GC
authors: Blobe
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008819:Mice, Nude; D009154:Mutation; D011509:Proteoglycans / Q000235:genetics / Q000378:metabolism*; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D053782:Transforming Growth Factor beta3 / Q000235:genetics / Q000378:metabolism*
chemical_list: D011509:Proteoglycans; D018125:Receptors, Transforming Growth Factor beta; D053782:Transforming Growth Factor beta3; C071736:betaglycan