title: Ectodomain shedding of FLT3 ligand is mediated by TNF-alpha converting enzyme.
abstract: FLT3 ligand (FLT3L) has diverse roles in the hematopoietic system, which include stimulating proliferation of hematopoietic precursors and development of NK cells and dendritic cells. FLT3L is initially synthesized as a membrane-bound protein, which must be cleaved to become a soluble growth factor. However, little is known about the enzyme involved in the proteolytic release of FLT3L. In the current study, we show that shedding of FLT3L is metalloprotease-dependent, and that this proteolytic activity was abolished in fibroblasts lacking TNF-alpha converting enzyme (TACE) and could be rescued by reintroducing wild-type TACE in these cells. Moreover, we found that cells derived from the thymus of conditional TACE-deficient mice produce less FLT3L, and that serum FLT3L levels in these TACE mutant mice are significantly lower, both after LPS treatment and in the absence of such a challenge, further corroborating the relevance of TACE as FLT3L sheddase in vivo. Considering the involvements of FLT3 and FLT3L in hematopoietic malignancies and stem cell mobilization, the identification of the enzyme involved in FLT3L shedding may have important clinical implications.
authors.affiliation: Department of Anti-aging Orthopedic Research, Keio University, School of Medicine, Shinjuku-ku, Tokyo, Japan. horiuchi@z3.keio.jp
authors.forename: Keisuke
authors.initials: K
authors.lastname: Horiuchi
authors.forename: Hideo
authors.initials: H
authors.lastname: Morioka
authors.forename: Hironari
authors.initials: H
authors.lastname: Takaishi
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Akiyama
authors.forename: Carl P
authors.initials: CP
authors.lastname: Blobel
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Toyama
mesh_terms: D051722:ADAM Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000072198:ADAM17 Protein; D000595:Amino Acid Sequence; D000818:Animals; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004789:Enzyme Activation / Q000187:drug effects; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D045726:Metalloproteases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D012995:Solubility; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology / Q000378:metabolism
chemical_list: D008565:Membrane Proteins; C084881:flt3 ligand protein; D045726:Metalloproteases; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse; D013755:Tetradecanoylphorbol Acetate