Cell surface colony-stimulating factor 1 can be cleaved by TNF-α converting enzyme or endocytosed in a clathrin-dependent manner

Keisuke Horiuchi, Takeshi Miyamoto, Hironari Takaishi, Akihiro Hakozaki, Naoto Kosaki, Yoshiteru Miyauchi, Mitsuru Furukawa, Jiro Takito, Hironori Kaneko, Kenichiro Matsuzaki, Hideo Morioka, Carl P. Blobel, Yoshiaki Toyama

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36 Citations (Scopus)

Abstract

CSF-1 is a hemopoietic growth factor, which plays an essential role in macrophage and osteoclast development. Alternative splice variants of CSF-1 are synthesized as soluble or membrane-anchored molecules, although membrane CSF-1 (mCSF-1) can be cleaved from the cell membrane to become soluble CSF-1. The activities involved in this proteolytic processing, also referred to as ectodomain shedding, remain poorly characterized. In the present study, we examined the properties of the mCSF-1 sheddase in cell-based assays. Shedding of mCSF-1 was up-regulated by phorbol ester treatment and was inhibited by the metalloprotease inhibitors GM6001 and tissue inhibitor of metalloproteases 3. Moreover, the stimulated shedding of mCSF-1 was abrogated in fibroblasts lacking the TNF-α converting enzyme (TACE, also known as a disintegrin and metalloprotease 17) and was rescued by expression of wild-type TACE in these cells, strongly suggesting that the stimulated shedding is TACE dependent. Additionally, we observed that mCSF-1 is predominantly localized to intracellular membrane compartments and is efficiently internalized in a clathrin-dependent manner. These results indicate that the local availability of mCSF-1 is actively regulated by ectodomain shedding and endocytosis. This mechanism may have important implications for the development and survival of monocyte lineage cells.

Original languageEnglish
Pages (from-to)6715-6724
Number of pages10
JournalJournal of Immunology
Volume179
Issue number10
DOIs
Publication statusPublished - 2007 Nov 15

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Horiuchi, K., Miyamoto, T., Takaishi, H., Hakozaki, A., Kosaki, N., Miyauchi, Y., Furukawa, M., Takito, J., Kaneko, H., Matsuzaki, K., Morioka, H., Blobel, C. P., & Toyama, Y. (2007). Cell surface colony-stimulating factor 1 can be cleaved by TNF-α converting enzyme or endocytosed in a clathrin-dependent manner. Journal of Immunology, 179(10), 6715-6724. https://doi.org/10.4049/jimmunol.179.10.6715