Plasminogen Receptors and Fibrinolysis

Miles, Lindsey A.; Ny, Lina; Wilczyńska, Małgorzata; Shen, Yue; Ny, Tor; Parmer, Robert J.

doi:10.3390/ijms22041712

Cited by 23 publications

(19 citation statements)

References 89 publications

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“…The plasminogen receptors function to stimulate tPA- and uPA-dependent plasminogen activation. In addition, they localize plasmin proteolytic activity to the cell surface and also protect both the plasminogen activators and plasmin from rapid inactivation by the abundant inhibitors that surround cells (reviewed in [ 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 ]). Plasminogen receptors are broadly distributed on both eukaryotic and prokaryotic cell types, and the majority of cells have a high capacity for binding plasminogen.…”

Section: Plasminogen Receptorsmentioning

confidence: 99%

The ANXA2/S100A10 Complex—Regulation of the Oncogenic Plasminogen Receptor

2021

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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.

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Section: Plasminogen Receptorsmentioning

confidence: 99%

The ANXA2/S100A10 Complex—Regulation of the Oncogenic Plasminogen Receptor

2021

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“…Plasmin generation proceeds at a slow rate but is accelerated by a group of cell surface proteins that bind plasminogen, called plasminogen receptors [55][56][57]. Plasminogen receptors localize the bound plasminogen near the vicinity of the tumor cell, allowing easy access by uPAR-bound uPA.…”

Section: Overview Of the Plasmin-plasminogen Activation Systemmentioning

confidence: 99%

“…Those that have a C-terminal lysine include αenolase [142], histone H2B [147,148], S100A4 [149], the annexin A2 heterotetramer (annexin A2 in complex with p11 also known as AIIt) [101], plasminogen (Plg)-RKT [150], TIP49a [151], and cytokeratin 8 [152]. Examples of plasminogen receptors that do not have the classic C-terminal lysine residue include high mobility group box-1 protein (HMGB-1) [56] (also known as amphoterin) and integrins, primarily those of the β2 inte-grin family [57] and glucose-regulated protein 78 [153]. It has been shown that a significant amount of the plasmin generating activity of malignant cancer cells is due to a novel, unidentified class of plasminogen receptors.…”

Section: Plasminogen Receptorsmentioning

confidence: 99%

Plasmin and Plasminogen System in the Tumor Microenvironment: Implications for Cancer Diagnosis, Prognosis, and Therapy

Bharadwaj

Holloway

Miller

et al. 2021

Cancers

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The tumor microenvironment (TME) is now being widely accepted as the key contributor to a range of processes involved in cancer progression from tumor growth to metastasis and chemoresistance. The extracellular matrix (ECM) and the proteases that mediate the remodeling of the ECM form an integral part of the TME. Plasmin is a broad-spectrum, highly potent, serine protease whose activation from its precursor plasminogen is tightly regulated by the activators (uPA, uPAR, and tPA), the inhibitors (PAI-1, PAI-2), and plasminogen receptors. Collectively, this system is called the plasminogen activation system. The expression of the components of the plasminogen activation system by malignant cells and the surrounding stromal cells modulates the TME resulting in sustained cancer progression signals. In this review, we provide a detailed discussion of the roles of plasminogen activation system in tumor growth, invasion, metastasis, and chemoresistance with specific emphasis on their role in the TME. We particularly review the recent highlights of the plasminogen receptor S100A10 (p11), which is a pivotal component of the plasminogen activation system.

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“…It was shown that tPA could interact with Plg-R kt to promote PLG activation and local plasmin generation. This pathway could increase the proinflammatory effects induced by plasmin [82] . So, these different studies highlight diverse and sometimes opposite effects of tPA versus plasmin in activation of macrophages by LPS in vitro .…”

Section: Effects Of Tpa On Mononuclear Phagocyte Cellsmentioning

confidence: 99%