Activation profiles of human kallikrein-related peptidases by proteases of the thrombostasis axis

Hyesook Yoon, Sachiko I. Blaber, D. Michael Evans, Julie Trim, Maria Aparecida Juliano, Isobel A. Scarisbrick, Michael Blaber

Research output: Contribution to journalArticle

38 Scopus citations

Abstract

The human kallikrein-related peptidases (KLKs) comprise 15 members (KLK1-15) and are the single largest family of serine proteases. The KLKs are utilized, or proposed, as clinically important biomarkers and therapeutic targets of interest in cancer and neurodegenerative disease. All KLKs appear to be secreted as inactive pro-forms (pro-KLKs) that are activated extracellularly by specific proteolytic release of their N-terminal pro-peptide. This processing is a key step in the regulation of KLK function. Much recent work has been devoted to elucidating the potential for activation cascades between members of the KLK family, with physiologically relevant KLK regulatory cascades now described in skin desquamation and semen liquefaction. Despite this expanding knowledge of KLK regulation, details regarding the potential for functional intersection of KLKs with other regulatory proteases are essentially unknown. To elucidate such interaction potential, we have characterized the ability of proteases associated with thrombostasis to hydrolyze the pro-peptide sequences of the KLK family using a previously described pro-KLK fusion protein system. A subset of positive hydrolysis results were subsequently quantified with proteolytic assays using intact recombinant pro-KLK proteins. Pro-KLK6 and 14 can be activated by both plasmin and uPA, with plasmin being the best activator of pro-KLK6 identified to date. Pro-KLK11 and 12 can be activated by a broad-spectrum of thrombostasis proteases, with thrombin exhibiting a high degree of selectivity for pro-KLK12. The results show that proteases of the thrombostasis family can efficiently activate specific pro-KLKs, demonstrating the potential for important regulatory interactions between these two major protease families. Published by Cold Spring Harbor Laboratory Press.

Original languageEnglish (US)
Pages (from-to)1998-2007
Number of pages10
JournalProtein Science
Volume17
Issue number11
DOIs
StatePublished - Nov 2008

Keywords

  • Activation cascade
  • Inflammation
  • KLK
  • Kallikrein-related peptidases
  • Plasmin
  • Thrombin
  • Thrombostasis

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology

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