Universität zu Köln

Portelli, Michael A., Siedlinski, Mateusz ORCID: 0000-0001-7682-6122, Stewart, Ceri E., Postma, Dirkje S., Nieuwenhuis, Maartje A., Vonk, Judith M., Nurnberg, Peter, Altmuller, Janine, Moffatt, Miriam F., Wardlaw, Andrew J., Parker, Stuart G., Connolly, Martin J., Koppelman, Gerard H. and Sayers, Ian ORCID: 0000-0001-5601-5410 (2014). Genome-wide protein QTL mapping identifies human plasma kallikrein as a post-translational regulator of serum uPAR levels. Faseb J., 28 (2). S. 923 - 935. BETHESDA: FEDERATION AMER SOC EXP BIOL. ISSN 1530-6860

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Abstract

The soluble cleaved urokinase plasminogen activator receptor (scuPAR) is a circulating protein detected in multiple diseases, including various cancers, cardiovascular disease, and kidney disease, where elevated levels of scuPAR have been associated with worsening prognosis and increased disease aggressiveness. We aimed to identify novel genetic and biomolecular mechanisms regulating scuPAR levels. Elevated serum scuPAR levels were identified in asthma (n=514) and chronic obstructive pulmonary disease (COPD; n=219) cohorts when compared to controls (n=96). In these cohorts, a genome-wide association study of serum scuPAR levels identified a human plasma kallikrein gene (KLKB1) promoter polymorphism (rs4253238) associated with serum scuPAR levels in a control/asthma population (P=1.17x10(-7)), which was also observed in a COPD population (combined P=5.04x10(-12)). Using a fluorescent assay, we demonstrated that serum KLKB1 enzymatic activity was driven by rs4253238 and is inverse to scuPAR levels. Biochemical analysis identified that KLKB1 cleaves scuPAR and negates scuPAR's effects on primary human bronchial epithelial cells (HBECs) in vitro. Chymotrypsin was used as a proproteolytic control, while basal HBECs were used as a control to define scuPAR-driven effects. In summary, we reveal a novel post-translational regulatory mechanism for scuPAR using a hypothesis-free approach with implications for multiple human diseases.Portelli, M. A., Siedlinski, M., Stewart, C. E., Postma, D. S., Nieuwenhuis, M. A., Vonk, J. M., Nurnberg, P., Altmuller, J., Moffatt, M. F., Wardlaw, A. J., Parker, S. G., Connolly, M. J., Koppelman, G. H., Sayers, I. Genome-wide protein QTL mapping identifies human plasma kallikrein as a post-translational regulator of serum uPAR levels.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Portelli, Michael A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Siedlinski, Mateusz UNSPECIFIED orcid.org/0000-0001-7682-6122 UNSPECIFIED Stewart, Ceri E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Postma, Dirkje S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Nieuwenhuis, Maartje A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Vonk, Judith M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Nurnberg, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Altmuller, Janine UNSPECIFIED UNSPECIFIED UNSPECIFIED Moffatt, Miriam F. UNSPECIFIED UNSPECIFIED UNSPECIFIED Wardlaw, Andrew J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Parker, Stuart G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Connolly, Martin J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Koppelman, Gerard H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Sayers, Ian UNSPECIFIED orcid.org/0000-0001-5601-5410 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-447594
DOI:	10.1096/fj.13-240879
Journal or Publication Title:	Faseb J.
Volume:	28
Number:	2
Page Range:	S. 923 - 935
Date:	2014
Publisher:	FEDERATION AMER SOC EXP BIOL
Place of Publication:	BETHESDA
ISSN:	1530-6860
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language PLASMINOGEN-ACTIVATOR RECEPTOR; UROKINASE RECEPTOR; PLAUR POLYMORPHISMS; NEUTROPHIL ELASTASE; CELL-PROLIFERATION; LUNG-FUNCTION; ASSOCIATION; SYSTEM; AIRWAY; MEMBRANE Multiple languages Biochemistry & Molecular Biology; Biology; Cell Biology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/44759