Ectodomain shedding of FLT3 ligand is mediated by TNF-α converting enzyme

Keisuke Horiuchi, Hideo Morioka, Hironari Takaishi, Haruhiko Akiyama, Carl P. Blobel, Yoshiaki Toyama

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15 Citations (Scopus)

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-α 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.

Original languageEnglish
Pages (from-to)7408-7414
Number of pages7
JournalJournal of Immunology
Volume182
Issue number12
DOIs
Publication statusPublished - 2009 Jun 15

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Horiuchi, K., Morioka, H., Takaishi, H., Akiyama, H., Blobel, C. P., & Toyama, Y. (2009). Ectodomain shedding of FLT3 ligand is mediated by TNF-α converting enzyme. Journal of Immunology, 182(12), 7408-7414. https://doi.org/10.4049/jimmunol.0801931