In vitro evidence that KLK14 regulates the components of the HGF/Met axis, pro-HGF and HGF-activator inhibitor 1A and 1B
-
Janet C. Reid
, Nigel C. Bennett , Carson R. Stephens , Melanie L. Carroll , Viktor Magdolen , Judith A. Clements and John D. Hooper
Abstract
Kallikrein-related peptidase (KLK) 14 is a serine protease linked to several pathologies including prostate cancer. We show that KLK14 has biphasic effects in vitro on activating and inhibiting components of the prostate cancer associated hepatocyte growth factor (HGF)/Met system. At 5–10 nm, KLK14 converts pro-HGF to the two-chain heterodimer required for Met activation, while higher concentrations degrade the HGF α-chain. HGF activator-inhibitor (HAI)-1A and HAI-1B, which inhibit pro-HGF activators, are degraded by KLK14 when protease:inhibitor stoichiometry is 1:1 or the protease is in excess. When inhibitors are in excess, KLK14 generates HAI-1A and HAI-1B fragments known to inhibit pro-HGF activating serine proteases. These in vitro data suggest that increased KLK14 activity could contribute at multiple levels to HGF/Met-mediated processes in prostate and other cancers.
Funding source: National Health and Medical Research Council
Award Identifier / Grant number: 614206
Funding source: Cancer Council Queensland
Award Identifier / Grant number: APP1021827
Funding source: Prostate Cancer Foundation of Australia
Award Identifier / Grant number: PG 3810
Funding source: Australian Research Council
Award Identifier / Grant number: FT120100917
Funding statement: We thank Dr. Yaowu He (University of Queensland) for technical advice, and Dr. Daniel Kirchhofer (Genentech) for the generous gift of recombinant hepsin, HAI-1A and HAI-1B. This work was supported by funding from the National Health and Medical Research Council of Australia (grant 614206), Cancer Council Queensland (grant APP1021827), Prostate Cancer Foundation of Australia (grant PG 3810) and Australian Research Council (Future Fellowship FT120100917) to J.D.H., a mobility grant (Personalized Medicine) from the German Academic Exchange Service (DAAD) to J.A.C., V.M., and J.D.H., a National Health and Medical Research Council of Australia Principal Research Fellowship to J.A.C., and an Australian Postgraduate Award, and Smart State PhD stipend and Queensland University of Technology top-up and write-up scholarships to J.C.R.
Acknowledgments
We thank Dr. Yaowu He (University of Queensland) for technical advice, and Dr. Daniel Kirchhofer (Genentech) for the generous gift of recombinant hepsin, HAI-1A and HAI-1B. This work was supported by funding from the National Health and Medical Research Council of Australia (grant 614206), Cancer Council Queensland (grant APP1021827), Prostate Cancer Foundation of Australia (grant PG 3810) and Australian Research Council (Future Fellowship FT120100917) to J.D.H., a mobility grant (Personalized Medicine) from the German Academic Exchange Service (DAAD) to J.A.C., V.M., and J.D.H., a National Health and Medical Research Council of Australia Principal Research Fellowship to J.A.C., and an Australian Postgraduate Award, and Smart State PhD stipend and Queensland University of Technology top-up and write-up scholarships to J.C.R.
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Article note:
This article was submitted for the Highlight Issue in connection with the 9th General Meeting 2015 of the International Proteolysis Society, published in issue 9 (2016) of Biological Chemistry.
©2016 Walter de Gruyter GmbH, Berlin/Boston
Articles in the same Issue
- Frontmatter
- Guest Editorial
- Highlight: remodelling the KLK landscape down under
- HIGHLIGHT: 6TH INTERNATIONAL SYMPOSIUM ON KALLIKREINS AND KALLIKREIN-RELATED PEPTIDASES
- Kallikrein(K1)-kinin-kininase (ACE) and end-organ damage in ischemia and diabetes: therapeutic implications
- Mechanistic insight from murine models of Netherton syndrome
- Development of molecules stimulating the activity of KLK3 – an update
- Exploring the active site binding specificity of kallikrein-related peptidase 5 (KLK5) guides the design of new peptide substrates and inhibitors
- Structural basis for the Zn2+ inhibition of the zymogen-like kallikrein-related peptidase 10
- Clinical relevance of kallikrein-related peptidase 6 (KLK6) and 8 (KLK8) mRNA expression in advanced serous ovarian cancer
- Kallikrein-related peptidase 6 exacerbates disease in an autoimmune model of multiple sclerosis
- A viable mouse model for Netherton syndrome based on mosaic inactivation of the Spink5 gene
- Therapeutic modulation of tissue kallikrein expression
- In vitro evidence that KLK14 regulates the components of the HGF/Met axis, pro-HGF and HGF-activator inhibitor 1A and 1B
- A computational analysis of the genetic and transcript diversity at the kallikrein locus
- Reviews
- Lymphocyte signaling and activation by the CARMA1-BCL10-MALT1 signalosome
- The power, pitfalls and potential of the nanodisc system for NMR-based studies
- Research Articles/Short Communications
- Cell Biology and Signaling
- Synergistic induction of cardiomyocyte differentiation from human bone marrow mesenchymal stem cells by interleukin 1β and 5-azacytidine
Articles in the same Issue
- Frontmatter
- Guest Editorial
- Highlight: remodelling the KLK landscape down under
- HIGHLIGHT: 6TH INTERNATIONAL SYMPOSIUM ON KALLIKREINS AND KALLIKREIN-RELATED PEPTIDASES
- Kallikrein(K1)-kinin-kininase (ACE) and end-organ damage in ischemia and diabetes: therapeutic implications
- Mechanistic insight from murine models of Netherton syndrome
- Development of molecules stimulating the activity of KLK3 – an update
- Exploring the active site binding specificity of kallikrein-related peptidase 5 (KLK5) guides the design of new peptide substrates and inhibitors
- Structural basis for the Zn2+ inhibition of the zymogen-like kallikrein-related peptidase 10
- Clinical relevance of kallikrein-related peptidase 6 (KLK6) and 8 (KLK8) mRNA expression in advanced serous ovarian cancer
- Kallikrein-related peptidase 6 exacerbates disease in an autoimmune model of multiple sclerosis
- A viable mouse model for Netherton syndrome based on mosaic inactivation of the Spink5 gene
- Therapeutic modulation of tissue kallikrein expression
- In vitro evidence that KLK14 regulates the components of the HGF/Met axis, pro-HGF and HGF-activator inhibitor 1A and 1B
- A computational analysis of the genetic and transcript diversity at the kallikrein locus
- Reviews
- Lymphocyte signaling and activation by the CARMA1-BCL10-MALT1 signalosome
- The power, pitfalls and potential of the nanodisc system for NMR-based studies
- Research Articles/Short Communications
- Cell Biology and Signaling
- Synergistic induction of cardiomyocyte differentiation from human bone marrow mesenchymal stem cells by interleukin 1β and 5-azacytidine