title: Inactivating mutations block the tumor necrosis factor-alpha-converting enzyme in the early secretory pathway.
abstract: The ectodomain of different transmembrane molecules is released by a proteolytic event known as shedding. The metalloprotease disintegrin proTNF-alpha converting enzyme (TACE) is responsible for the shedding of various proteins, including protransforming growth factor-alpha (proTGF-alpha) and amyloid-beta precursor protein (APP). Inactive TACE accumulates in the early secretory pathway of cell mutants (M1 and M2) defective in proTGF-alpha and APP shedding. Although previous evidences indicated that the component mutated in M1 and M2 cells is different from TACE, recent results show the existence of two heterozygous point mutations in TACE from M2 cells. Here, we show that wild-type TACE stably transfected in M2 cells is processed, transported to the cell surface, and rescues the proTGF-alpha and APP shedding-defective phenotype. Furthermore, M1 cells also express mutant TACE and transfection with wild-type TACE restores the wild-type phenotype. Therefore, different inactivating mutations result in the accumulation of TACE in the early secretory pathway, emphasizing the importance of the initial steps in the biosynthesis of TACE.
authors.affiliation: Laboratori de Recerca Oncològica, Servei d'Oncologia Mèdica, Hospital Universitari Vall d'Hebron, Psg. Vall d'Hebron 119-129, 08035, Barcelona, Spain.
authors.forename: Teresa
authors.initials: T
authors.lastname: Villanueva de la Torre
authors.forename: Joan J
authors.initials: JJ
authors.lastname: Bech-Serra
authors.forename: Soraya
authors.initials: S
authors.lastname: Ruiz-Paz
authors.forename: Josep
authors.initials: J
authors.lastname: Baselga
authors.forename: Joaquín
authors.initials: J
authors.lastname: Arribas
mesh_terms: D051722:ADAM Proteins; D000072198:ADAM17 Protein; D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D008666:Metalloendopeptidases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D010641:Phenotype; D017386:Sequence Homology, Amino Acid; D014162:Transfection
chemical_list: D051722:ADAM Proteins; D008666:Metalloendopeptidases; D000072198:ADAM17 Protein