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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| Format: | Article |
| Language: | English |
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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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| author | Manon Bulliard Katarina Pinjusic Laura Iacobucci Céline Schmuziger Nadine Fournier Daniel B. Constam |
| author_facet | Manon Bulliard Katarina Pinjusic Laura Iacobucci Céline Schmuziger Nadine Fournier Daniel B. Constam |
| author_sort | Manon Bulliard |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-c67c055efa3e44abbc70a7be3d499912 |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-c67c055efa3e44abbc70a7be3d4999122025-08-20T02:56:11ZengNature PortfolioNature Communications2041-17232025-03-0116111810.1038/s41467-025-57661-5Kallikrein-8 mediates furin-independent Activin-A precursor processing to stimulate tumor growth in melanomaManon Bulliard0Katarina Pinjusic1Laura Iacobucci2Céline Schmuziger3Nadine Fournier4Daniel B. Constam5École Polytechnique Fédérale de Lausanne (EPFL) SV ISREC, Station 19École Polytechnique Fédérale de Lausanne (EPFL) SV ISREC, Station 19École Polytechnique Fédérale de Lausanne (EPFL) SV ISREC, Station 19École Polytechnique Fédérale de Lausanne (EPFL) SV ISREC, Station 19École Polytechnique Fédérale de Lausanne (EPFL) SV ISREC, Station 19École Polytechnique Fédérale de Lausanne (EPFL) SV ISREC, Station 19Abstract 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.https://doi.org/10.1038/s41467-025-57661-5 |
| spellingShingle | Manon Bulliard Katarina Pinjusic Laura Iacobucci Céline Schmuziger Nadine Fournier Daniel B. Constam Kallikrein-8 mediates furin-independent Activin-A precursor processing to stimulate tumor growth in melanoma Nature Communications |
| title | Kallikrein-8 mediates furin-independent Activin-A precursor processing to stimulate tumor growth in melanoma |
| title_full | Kallikrein-8 mediates furin-independent Activin-A precursor processing to stimulate tumor growth in melanoma |
| title_fullStr | Kallikrein-8 mediates furin-independent Activin-A precursor processing to stimulate tumor growth in melanoma |
| title_full_unstemmed | Kallikrein-8 mediates furin-independent Activin-A precursor processing to stimulate tumor growth in melanoma |
| title_short | Kallikrein-8 mediates furin-independent Activin-A precursor processing to stimulate tumor growth in melanoma |
| title_sort | kallikrein 8 mediates furin independent activin a precursor processing to stimulate tumor growth in melanoma |
| url | https://doi.org/10.1038/s41467-025-57661-5 |
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