Activation profiles of human kallikrein-related peptidases by proteases of the thrombostasis axis
- 31 October 2008
- journal article
- research article
- Published by Wiley in Protein Science
- Vol. 17 (11), 1998-2007
- https://doi.org/10.1110/ps.036715.108
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
This publication has 93 references indexed in Scilit:
- Kallikreins are associated with secondary progressive multiple sclerosis and promote neurodegenerationBiological Chemistry, 2008
- Kallikrein 6 Induces E-Cadherin Shedding and Promotes Cell Proliferation, Migration, and InvasionCancer Research, 2007
- Fibrin deposition accelerates neurovascular damage and neuroinflammation in mouse models of Alzheimer's diseaseThe Journal of Experimental Medicine, 2007
- The Autolytic Regulation of Human Kallikrein-Related Peptidase 6Biochemistry, 2007
- Serine Protease Activity and Residual LEKTI Expression Determine Phenotype in Netherton SyndromeJournal of Investigative Dermatology, 2006
- Activation of latent protease function of pro‐hk2, but not pro‐PSA, involves autoprocessingThe Prostate, 2001
- Activation of the Zymogen Form of Prostate-Specific Antigen by Human Glandular Kallikrein 2Biochemical and Biophysical Research Communications, 1997
- Characterization of the Precursor of Prostate-specific AntigenPublished by Elsevier BV ,1997
- The chymotrypsin‐like activity of human prostate‐specific antigen, γ‐seminoproteinFEBS Letters, 1987
- Prostate-Specific Antigen as a Serum Marker for Adenocarcinoma of the ProstateNew England Journal of Medicine, 1987