Kallikrein-8 mediates furin-independent Activin-A precursor processing to stimulate tumor growth in melanoma

Manon Bulliard, Katarina Pinjusic, Laura Iacobucci, Céline Schmuziger, Nadine Fournier and Daniel B. Constam ()
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Manon Bulliard: Station 19
Katarina Pinjusic: Station 19
Laura Iacobucci: Station 19
Céline Schmuziger: Station 19
Nadine Fournier: Station 19
Daniel B. Constam: Station 19

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-57661-5

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