RRC ID 43169
Author Horiuchi K, Miyamoto T, Takaishi H, Hakozaki A, Kosaki N, Miyauchi Y, Furukawa M, Takito J, Kaneko H, Matsuzaki K, Morioka H, Blobel CP, Toyama Y.
Title Cell surface colony-stimulating factor 1 can be cleaved by TNF-alpha converting enzyme or endocytosed in a clathrin-dependent manner.
Journal J Immunol
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-alpha 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.
Volume 179(10)
Pages 6715-24
Published 2007-11-15
DOI 10.4049/jimmunol.179.10.6715
PII 179/10/6715
PMID 17982061
MeSH ADAM Proteins / antagonists & inhibitors ADAM Proteins / metabolism* ADAM17 Protein Alternative Splicing / drug effects Alternative Splicing / physiology Animals COS Cells Carcinogens / pharmacology Cell Survival / drug effects Cell Survival / physiology Chlorocebus aethiops Clathrin / metabolism* Dipeptides / pharmacology Endocytosis / physiology* Macrophage Colony-Stimulating Factor / metabolism* Macrophages / metabolism* Membrane Proteins / metabolism Mice Osteoclasts / metabolism* Phorbol Esters / pharmacology Protease Inhibitors / pharmacology Protein Structure, Tertiary / physiology Tissue Inhibitor of Metalloproteinase-3 / metabolism
IF 4.886
Times Cited 34
Human and Animal Cells ST2(RCB0224) COS-7(RCB0539)