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Ectodomain Shedding of FLT3 Ligand Is Mediated by TNF- Converting Enzyme¹

Keisuke Horiuchi^2,*,, Hideo Morioka, Hironari Takaishi, Haruhiko Akiyama, Carl P. Blobel and Yoshiaki Toyama

^* Department of Anti-aging Orthopedic Research, Department of Orthopedic Surgery, Keio University, School of Medicine, Shinjuku-ku, Tokyo, Japan; Department of Orthopedics, Kyoto University, Konoe-cho, Yoshida Sakyo-ku, Kyoto, Japan; and Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, NY 10021

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- 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by The Uehara Memorial Foundation, The Mochida Memorial Foundation, and Grants-in-aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (19591765) (to K.H.), and NIH GM064750 (to C.P.B.).

² Address correspondence and reprint requests to Dr. Keisuke Horiuchi, Department of Orthopedic Surgery, Keio University, School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, Japan. E-mail address: horiuchi{at}z3.keio.jp

³ Abbreviations used in this paper: FLT3, fms-like tyrosine kinase 3; FLT3L, FLT3 ligand; KITL, c-kit ligand; TACE, TNF- converting enzyme; WT, wild type; ADAM, a disintegrin and metalloprotease; AP, alkaline phosphatase; 5-FU, fluorouracil; TIMP, tissue inhibitor of metalloprotease; mEF, mouse embryonic fibroblasts; STI, trypsin inhibitor from Glycine max; HA, hemagglutination.