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Biomolecules
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Plasminogen, Plasminogen Receptors and Binding Mechanisms in Cancer
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Plasminogen, Plasminogen Receptors and Binding Mechanisms in Cancer

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Medicine".

Deadline for manuscript submissions: closed (15 December 2021) | Viewed by 16670

Special Issue Editors

Dr. Ruby Law

E-Mail Website
Guest Editor
Monash Biomedicine Discovery Institute, Monash University, Melbourne 3800, Australia
Interests: structure–function; receptor binding; protease and inhibitor; pore-forming toxin; neurotransmitter and inhibitor
Dr. Eleanor Leung

E-Mail Website
Guest Editor
Monash Biomedicine Institute, Department of Biochemistry and Molecular Biology, Monash University, Melbourne 3800, Australia
Interests: biochemistry; molecular biology; cell biology; fragment-based drug discovery; biophysical chemistry; immunology; protein engineering; directed evolution; enzymology; genetics

Special Issue Information

Dear Colleagues,

Plasminogen is one of the most abundant zymogens found in mammals. The conversion of plasminogen to its proteolytic active protease, plasmin, often occurs in the presence of an activator and only after its binding to cell surface receptors or extracellular matrices. Although plasmin is a highly reactive protease with promiscuous substrate specificity, its proteolytic activity is restricted to the vicinity of those targets bound to plasmin. Plasmin cleaves substrates such as fibrin, growth factors, hormones, complements and extracellular matrices; plasmin also activates other proteases and a cascade of components of the coagulation pathway. Conversely, plasminogen and plasmin play essential roles in many physiological functions, such as in wound healing, inflammation, angiogenesis, embryogenesis and cell migration.

Pathogens such as Streptococcus, Staphylococcus, Yersinia and Influenza virus are well known for their receptor-mediated and specific binding to plasminogen and plasmin as a way to promote invasion and dissemination. It may not be surprising that plasminogen and plasmin play key roles in mediating cancer invasion and metastasis through their capacity to bind to cell receptors, promoting angiogenesis and cell migration.

In this Special Issue, we would like to capture the recent developments in the understanding of the roles of plasminogen and plasmin in cancer. Original manuscripts, reviews, communications and commentaries on the recent developments related to aspects of plasminogen and plasmin receptor binding and cancer are most welcome.

Dr. Ruby Law
Dr. Eleanor Leung
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • plasminogen and plasmin
  • cell receptor
  • cancer
  • metastasis
  • inhibitor
  • diagnosis

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Published Papers (4 papers)

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Research

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10 pages, 2115 KiB  
Communication
Plg-RKT Expression in Human Breast Cancer Tissues
by Lindsey A. Miles, Stan Krajewski, Nagyung Baik, Robert J. Parmer and Barbara M. Mueller
Biomolecules 2022, 12(4), 503; https://doi.org/10.3390/biom12040503 - 26 Mar 2022
Cited by 3 | Viewed by 2314
Abstract
The plasminogen activation system regulates the activity of the serine protease, plasmin. The role of plasminogen receptors in cancer progression is being increasingly appreciated as key players in modulation of the tumor microenvironment. The interaction of plasminogen with cells to promote plasminogen activation [...] Read more.
The plasminogen activation system regulates the activity of the serine protease, plasmin. The role of plasminogen receptors in cancer progression is being increasingly appreciated as key players in modulation of the tumor microenvironment. The interaction of plasminogen with cells to promote plasminogen activation requires the presence of proteins exposing C-terminal lysines on the cell surface. Plg-RKT is a structurally unique plasminogen receptor because it is an integral membrane protein that is synthesized with and binds plasminogen via a C-terminal lysine exposed on the cell surface. Here, we have investigated the expression of Plg-RKT in human breast tumors and human breast cancer cell lines. Breast cancer progression tissue microarrays were probed with anti-Plg-RKT mAB and we found that Plg-RKT is widely expressed in human breast tumors, that its expression is increased in tumors that have spread to draining lymph nodes and distant organs, and that Plg-RKT expression is most pronounced in hormone receptor (HR)-positive tumors. Plg-RKT was detected by Western blotting in human breast cancer cell lines. By flow cytometry, Plg-RKT cell surface expression was highest on the most aggressive tumor cell line. Future studies are warranted to address the functions of Plg-RKT in breast cancer. Full article
(This article belongs to the Special Issue Plasminogen, Plasminogen Receptors and Binding Mechanisms in Cancer)
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12 pages, 1618 KiB  
Article
Histone 2B Facilitates Plasminogen-Enhanced Endothelial Migration through Protease-Activated Receptor 1 (PAR1) and Protease-Activated Receptor 2 (PAR2)
by Mitali Das, Sujay Subbayya Ithychanda and Edward F. Plow
Biomolecules 2022, 12(2), 211; https://doi.org/10.3390/biom12020211 - 26 Jan 2022
Cited by 4 | Viewed by 2522
Abstract
Plasminogen and its multiple receptors have been implicated in the responses of many different cell types. Among these receptors, histone 2B (H2B) has been shown to play a prominent role in macrophage responses. The contribution of H2B to plasminogen-induced endothelial migration, an event [...] Read more.
Plasminogen and its multiple receptors have been implicated in the responses of many different cell types. Among these receptors, histone 2B (H2B) has been shown to play a prominent role in macrophage responses. The contribution of H2B to plasminogen-induced endothelial migration, an event relevant to wound healing and angiogenesis, is unknown. Plasminogen enhanced the migration of endothelial cells, which was inhibited by both Protease-Activated Receptor-1 (PAR1) and 2 (PAR2) antagonists. H2B was detected on viable endothelial cells of venous and arterial origin, and an antibody to H2B that blocks plasminogen binding also inhibited the plasminogen-dependent migration by these cells. The antibody blockade was as effective as PAR1 or PAR2 antagonists in inhibiting endothelial cell migration. In pull-down experiments, H2B formed a complex with both PAR1 and PAR2 but not β3 integrin, another receptor implicated in endothelial migration in the presence of plasminogen. H2B was found to be associated with clathrin adapator protein, AP2µ (clathrin AP2µ) and β-arrestin2, which are central to the internationalization/signaling machinery of the PARs. These associations with PAR1-clathrin adaptor AP2µ- and PAR2-β-arrestin2-dependent internalization/signaling pathways provide a mechanism to link plasminogen to responses such as wound healing and angiogenesis. Full article
(This article belongs to the Special Issue Plasminogen, Plasminogen Receptors and Binding Mechanisms in Cancer)
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Review

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27 pages, 2062 KiB  
Review
The Urokinase Plasminogen Activation System in Pancreatic Cancer: Prospective Diagnostic and Therapeutic Targets
by Ashna A. Kumar, Benjamin J. Buckley and Marie Ranson
Biomolecules 2022, 12(2), 152; https://doi.org/10.3390/biom12020152 - 18 Jan 2022
Cited by 24 | Viewed by 7024
Abstract
Pancreatic cancer is a highly aggressive malignancy that features high recurrence rates and the poorest prognosis of all solid cancers. The urokinase plasminogen activation system (uPAS) is strongly implicated in the pathophysiology and clinical outcomes of patients with pancreatic ductal adenocarcinoma (PDAC), which [...] Read more.
Pancreatic cancer is a highly aggressive malignancy that features high recurrence rates and the poorest prognosis of all solid cancers. The urokinase plasminogen activation system (uPAS) is strongly implicated in the pathophysiology and clinical outcomes of patients with pancreatic ductal adenocarcinoma (PDAC), which accounts for more than 90% of all pancreatic cancers. Overexpression of the urokinase-type plasminogen activator (uPA) or its cell surface receptor uPAR is a key step in the acquisition of a metastatic phenotype via multiple mechanisms, including the increased activation of cell surface localised plasminogen which generates the serine protease plasmin. This triggers multiple downstream processes that promote tumour cell migration and invasion. Increasing clinical evidence shows that the overexpression of uPA, uPAR, or of both is strongly associated with worse clinicopathological features and poor prognosis in PDAC patients. This review provides an overview of the current understanding of the uPAS in the pathogenesis and progression of pancreatic cancer, with a focus on PDAC, and summarises the substantial body of evidence that supports the role of uPAS components, including plasminogen receptors, in this disease. The review further outlines the clinical utility of uPAS components as prospective diagnostic and prognostic biomarkers for PDAC, as well as a rationale for the development of novel uPAS-targeted therapeutics. Full article
(This article belongs to the Special Issue Plasminogen, Plasminogen Receptors and Binding Mechanisms in Cancer)
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34 pages, 2512 KiB  
Review
The ANXA2/S100A10 Complex—Regulation of the Oncogenic Plasminogen Receptor
by Alamelu G. Bharadwaj, Emma Kempster and David M. Waisman
Biomolecules 2021, 11(12), 1772; https://doi.org/10.3390/biom11121772 - 26 Nov 2021
Cited by 12 | Viewed by 3905
Abstract
The generation of the serine protease plasmin is initiated by the binding of its zymogenic precursor, plasminogen, to cell surface receptors. The proteolytic activity of plasmin, generated at the cell surface, plays a crucial role in several physiological processes, including fibrinolysis, angiogenesis, wound [...] Read more.
The generation of the serine protease plasmin is initiated by the binding of its zymogenic precursor, plasminogen, to cell surface receptors. The proteolytic activity of plasmin, generated at the cell surface, plays a crucial role in several physiological processes, including fibrinolysis, angiogenesis, wound healing, and the invasion of cells through both the basement membrane and extracellular matrix. The seminal observation by Albert Fischer that cancer cells, but not normal cells in culture, produce large amounts of plasmin formed the basis of current-day observations that plasmin generation can be hijacked by cancer cells to allow tumor development, progression, and metastasis. Thus, the cell surface plasminogen-binding receptor proteins are critical to generating plasmin proteolytic activity at the cell surface. This review focuses on one of the twelve well-described plasminogen receptors, S100A10, which, when in complex with its regulatory partner, annexin A2 (ANXA2), forms the ANXA2/S100A10 heterotetrameric complex referred to as AIIt. We present the theme that AIIt is the quintessential cellular plasminogen receptor since it regulates the formation and the destruction of plasmin. We also introduce the term oncogenic plasminogen receptor to define those plasminogen receptors directly activated during cancer progression. We then discuss the research establishing AIIt as an oncogenic plasminogen receptor-regulated during EMT and activated by oncogenes such as SRC, RAS, HIF1α, and PML-RAR and epigenetically by DNA methylation. We further discuss the evidence derived from animal models supporting the role of S100A10 in tumor progression and oncogenesis. Lastly, we describe the potential of S100A10 as a biomarker for cancer diagnosis and prognosis. Full article
(This article belongs to the Special Issue Plasminogen, Plasminogen Receptors and Binding Mechanisms in Cancer)
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