Scholarlink

<p>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 <i>Klk8</i> 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.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年3月10日

查看全文
  • Manon Bulliard,
  • Katarina Pinjusic,
  • Laura Iacobucci,
  • Céline Schmuziger,
  • Nadine Fournier,
  • Daniel B. Constam

摘要

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.