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

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

Author Yoon, Hyesook Google Scholar
Blaber, Sachiko I. Google Scholar
Evans, D. Michael Google Scholar
Trim, Julie Google Scholar
Juliano, Maria Aparecida Autor UNIFESP Google Scholar
Scarisbrick, Isobel A. Google Scholar
Blaber, Michael Google Scholar
Institution Florida State Univ
Vantia Ltd
Ferring Res Ltd
Universidade Federal de São Paulo (UNIFESP)
Mayo Med & Grad Sch
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.
Keywords kallikrein-related peptidases
KLK
activation cascade
thrombostasis
plasmin
thrombin
inflammation
Language English
Sponsor NIH
National Multiple Sclerosis Society
Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
Grant number NIH: 1R15NS057771-01
National Multiple Sclerosis Society: PP1113
National Multiple Sclerosis Society: RG3367
Date 2008-11-01
Published in Protein Science. Woodbury: Cold Spring Harbor Lab Press, Publications Dept, v. 17, n. 11, p. 1998-2007, 2008.
ISSN 0961-8368 (Sherpa/Romeo, impact factor)
Publisher Cold Spring Harbor Lab Press, Publications Dept
Extent 1998-2007
Origin http://dx.doi.org/10.1110/ps.036715.108
Access rights Open access Open Access
Type Article
Web of Science ID WOS:000260423400013
URI http://repositorio.unifesp.br/handle/11600/30981

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