Kallikrein-8 mediates furin-independent Activin-A precursor processing to stimulate tumor growth in melanoma
Abstract Receptor binding of TGF-β and related ligands such as Activin-A requires cleavage of a furin site in their dimeric precursor proteins. Melanoma cells cleave one Activin-A subunit independently of furin and related proprotein convertases, raising questions of how this half-processed intermed...
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| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-03-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-57661-5 |
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| Summary: | Abstract Receptor binding of TGF-β and related ligands such as Activin-A requires cleavage of a furin site in their dimeric precursor proteins. Melanoma cells cleave one Activin-A subunit independently of furin and related proprotein convertases, raising questions of how this half-processed intermediate is generated and whether it influences tumor growth. Here, an siRNA library screen for proteases mediating this furin-independent “hemicleavage” identifies kallikrein (Klk)-8. While a KLK8 cleavage site in proActivin-A overlaps with the furin recognition sequence, its exposure is limited and requires prior transient acidification. Therefore, only furin efficiently converts proActivin-A to fully mature form both in tumor cells and in cell-free cleavage assays. Moreover, knockdown of Klk8 in syngeneic melanoma grafts suppresses Activin-A induced tumor growth, demonstrating that cleavage by only furin is not sufficient. Besides elucidating how Activin-A processing is regulated, our findings show that KLK8 holds promise as a target to mitigate Activin-A induced tumor growth. |
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| ISSN: | 2041-1723 |