Organization, evolution and functions of the human and mouse Ly6/uPAR family genes

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Abstract

Members of the lymphocyte antigen-6 (Ly6)/urokinase-type plasminogen activator receptor (uPAR) superfamily of proteins are cysteine-rich proteins characterized by a distinct disulfide bridge pattern that creates the three-finger Ly6/uPAR (LU) domain. Although the Ly6/uPAR family proteins share a common structure, their expression patterns and functions vary. To date, 35 human and 61 mouse Ly6/uPAR family members have been identified. Based on their subcellular localization, these proteins are further classified as GPI-anchored on the cell membrane, or secreted. The genes encoding Ly6/uPAR family proteins are conserved across different species and are clustered in syntenic regions on human chromosomes 8, 19, 6 and 11, and mouse Chromosomes 15, 7, 17, and 9, respectively. Here, we review the human and mouse Ly6/uPAR family gene and protein structure and genomic organization, expression, functions, and evolution, and introduce new names for novel family members.

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Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation.

Hong. Wang, Man Yu, Mahendar Ochani … (2003)

Excessive inflammation and tumour-necrosis factor (TNF) synthesis cause morbidity and mortality in diverse human diseases including endotoxaemia, sepsis, rheumatoid arthritis and inflammatory bowel disease. Highly conserved, endogenous mechanisms normally regulate the magnitude of innate immune responses and prevent excessive inflammation. The nervous system, through the vagus nerve, can inhibit significantly and rapidly the release of macrophage TNF, and attenuate systemic inflammatory responses. This physiological mechanism, termed the 'cholinergic anti-inflammatory pathway' has major implications in immunology and in therapeutics; however, the identity of the essential macrophage acetylcholine-mediated (cholinergic) receptor that responds to vagus nerve signals was previously unknown. Here we report that the nicotinic acetylcholine receptor alpha7 subunit is required for acetylcholine inhibition of macrophage TNF release. Electrical stimulation of the vagus nerve inhibits TNF synthesis in wild-type mice, but fails to inhibit TNF synthesis in alpha7-deficient mice. Thus, the nicotinic acetylcholine receptor alpha7 subunit is essential for inhibiting cytokine synthesis by the cholinergic anti-inflammatory pathway.

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Regulation of cell signalling by uPAR.

Harvey Smith, Chris J Marshall (2010)

Urokinase-type plasminogen activator receptor (uPAR) expression is elevated during inflammation and tissue remodelling and in many human cancers, in which it frequently indicates poor prognosis. uPAR regulates proteolysis by binding the extracellular protease urokinase-type plasminogen activator (uPA; also known as urokinase) and also activates many intracellular signalling pathways. Coordination of extracellular matrix (ECM) proteolysis and cell signalling by uPAR underlies its important function in cell migration, proliferation and survival and makes it an attractive therapeutic target in cancer and inflammatory diseases. uPAR lacks transmembrane and intracellular domains and so requires transmembrane co-receptors for signalling. Integrins are essential uPAR signalling co-receptors and a second uPAR ligand, the ECM protein vitronectin, is also crucial for this process.

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PredGPI: a GPI-anchor predictor

Andrea Pierleoni, Pier Luigi Martelli, Rita Casadio (2008)

Background Several eukaryotic proteins associated to the extracellular leaflet of the plasma membrane carry a Glycosylphosphatidylinositol (GPI) anchor, which is linked to the C-terminal residue after a proteolytic cleavage occurring at the so called ω-site. Computational methods were developed to discriminate proteins that undergo this post-translational modification starting from their aminoacidic sequences. However more accurate methods are needed for a reliable annotation of whole proteomes. Results Here we present PredGPI, a prediction method that, by coupling a Hidden Markov Model (HMM) and a Support Vector Machine (SVM), is able to efficiently predict both the presence of the GPI-anchor and the position of the ω-site. PredGPI is trained on a non-redundant dataset of experimentally characterized GPI-anchored proteins whose annotation was carefully checked in the literature. Conclusion PredGPI outperforms all the other previously described methods and is able to correctly replicate the results of previously published high-throughput experiments. PredGPI reaches a lower rate of false positive predictions with respect to other available methods and it is therefore a costless, rapid and accurate method for screening whole proteomes.

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Author and article information

Contributors

Shivalingappa K. Swamynathan: 412-802-6437 , Swamynathansk@upmc.edu

Journal

Journal ID (nlm-ta): Hum Genomics

Journal ID (iso-abbrev): Hum. Genomics

Title: Human Genomics

Publisher: BioMed Central (London )

ISSN (Print): 1473-9542

ISSN (Electronic): 1479-7364

Publication date (Electronic): 21 April 2016

Publication date PMC-release: 21 April 2016

Publication date Collection: 2016

Volume: 10

Electronic Location Identifier: 10

Affiliations

[ ]Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, USA

[ ]HUGO Gene Nomenclature Committee (HGNC), European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SD UK

[ ]Mouse Genome Informatics, The Jackson Laboratory, Bar Harbor, ME 04609 USA

[ ]Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, USA

[ ]McGowan Institute of Regenerative Medicine, University of Pittsburgh, Pittsburgh, USA

[ ]Fox Center for Vision Restoration, University of Pittsburgh School of Medicine, Pittsburgh, USA

[ ]Eye and Ear Institute, University of Pittsburgh School of Medicine, 203 Lothrop Street, Room 1025, Pittsburgh, PA 15213 USA

Article

Publisher ID: 74

DOI: 10.1186/s40246-016-0074-2

PMC ID: 4839075

PubMed ID: 27098205

SO-VID: b82089c6-cb5d-41eb-bb4b-f4da81bc3072

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 11 January 2016

Date accepted : 14 April 2016

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;

Award ID: U41HG003345

Award ID: HG000330

Award Recipient : Elspeth A. Bruford Monica S. McAndrews

Funded by: FundRef http://dx.doi.org/http://dx.doi.org/10.13039/100000002, National Institutes of Health;

Award ID: P30 EY08098

Funded by: FundRef http://dx.doi.org/http://dx.doi.org/10.13039/100001818, Research to Prevent Blindness;

Funded by: FundRef http://dx.doi.org/http://dx.doi.org/10.13039/100002089, Fight for Sight;

Funded by: FundRef http://dx.doi.org/http://dx.doi.org/10.13039/100001607, Eye and Ear Foundation of Pittsburgh;

Funded by: FundRef http://dx.doi.org/10.13039/100004440, Wellcome Trust;

Award ID: 099129/Z/12/Z

Award Recipient : Elspeth A. Bruford

Custom metadata

ScienceOpen disciplines: Genetics

Keywords: ly6/upar family,lu domain,three-finger domain,upar,lymphocytes,neutrophils

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ScienceOpen disciplines: Genetics

Keywords: ly6/upar family, lu domain, three-finger domain, upar, lymphocytes, neutrophils

Organization, evolution and functions of the human and mouse Ly6/uPAR family genes

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Abstract

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RNA drug delivery

Most cited references 179

Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation.

Regulation of cell signalling by uPAR.

PredGPI: a GPI-anchor predictor

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