# PLAU

## Overview
The PLAU gene encodes the urokinase-type plasminogen activator (uPA), a serine protease that plays a pivotal role in the conversion of plasminogen to plasmin, a key enzyme in fibrinolysis and extracellular matrix degradation. This protein is synthesized as an inactive precursor and becomes active upon binding to its receptor, uPAR, on the cell surface, which localizes its proteolytic activity and initiates various signal transduction pathways (Ploug2003StructureFunction; Crippa2007Urokinasetype). uPA is involved in physiological processes such as wound healing and tissue remodeling, as well as pathological conditions, including cancer progression and metastasis, where it facilitates tumor cell invasion and migration (Hosen2022Metastatic; Vincenza2011The). The interaction of uPA with other proteins, such as TM4SF1 and uPAR, underscores its significance in cellular signaling and its potential as a therapeutic target in oncology and immune regulation (He2012PLAU; Zheng2024PLAU).

## Structure
The PLAU gene encodes the urokinase-type plasminogen activator (uPA), a serine protease involved in converting plasminogen to plasmin. The protein is synthesized as a single-chain molecule (scuPA) and can be enzymatically cleaved into a two-chain disulfide-linked form (tcuPA) with plasminogen activator activity (Beloglazova2013Structural). The primary structure of uPA includes a signal peptide, a growth factor-like domain (GFD), a kringle domain, and a serine protease domain (Hansen1994Solution).

The secondary structure of uPA features alpha helices and beta sheets. The GFD contains two regions of antiparallel beta-sheet and a beta-hairpin structure, with a seven-residue omega loop crucial for binding to the urokinase receptor (uPAR) (Hansen1994Solution; Beloglazova2013Structural). The kringle domain includes a two-stranded antiparallel beta-sheet and several reverse turns (Hansen1994Solution).

The tertiary structure involves the folding of these domains, with the GFD and kringle domains exhibiting structural independence and minimal interdomain interactions (Hansen1994Solution). The quaternary structure may involve interactions with uPAR, forming a stable complex with a dissociation constant of 0.28 nM (Huai2006Structure).

Post-translational modifications of uPA include glycosylation, which affects its molecular weight and interaction with uPAR (Ploug2003StructureFunction). Splice variants of uPA can result in different isoforms with distinct functions, although specific details on these variants are not provided in the context.

## Function
The PLAU gene encodes the urokinase-type plasminogen activator (uPA), a serine protease that plays a crucial role in the conversion of plasminogen to plasmin, an enzyme involved in the degradation of fibrin and extracellular matrix components. This process is essential for fibrinolysis, tissue remodeling, and cell migration (Vincenza2011The). In healthy human cells, uPA is involved in non-pathological processes such as wound healing, post-lactational involution, and trophoblast implantation (Crippa2007Urokinasetype). 

uPA is secreted as an inactive proenzyme and becomes active upon binding to its receptor, uPAR, on the cell surface. This binding localizes its proteolytic activity and triggers signal transduction pathways that can modulate apoptosis-related genes (Crippa2007Urokinasetype). The interaction between uPA and uPAR is critical for plasminogen activation and subsequent cellular processes, including tissue repair and regeneration (Vincenza2011The; Ploug2003StructureFunction). 

The uPA/uPAR system also plays a role in the mobilization and homing of hematopoietic stem cells, regulation of cell adhesion, and degradation of the extracellular matrix, which are essential for maintaining tissue homeostasis and facilitating repair processes (Vincenza2011The).

## Interactions
PLAU, or urokinase-type plasminogen activator, is involved in several protein interactions that influence its role in cancer progression and immune regulation. In non-small cell lung cancer (NSCLC), PLAU interacts with the protein TM4SF1. This interaction stabilizes TM4SF1, preventing its degradation and increasing its protein levels, which is crucial for the aggressive phenotype observed in NSCLC cells. The PLAU-TM4SF1 interaction is associated with the activation of Akt signaling, promoting cancer cell growth and survival (Zheng2024PLAU).

In pancreatic ductal adenocarcinoma (PDAC), PLAU is involved in a network of protein-protein interactions. It interacts with several positively correlated genes, including FN1, MMP2, GAPDH, CD44, and MMP9, which are associated with cancer progression pathways such as ECM degradation and epithelial-mesenchymal transition (Hosen2022Metastatic). PLAU also interacts with its receptor uPAR, facilitating intracellular signaling pathways that regulate cancer cell behaviors, including proliferation, migration, and invasion (Hosen2022Metastatic).

In the context of regulatory T cells (Tregs), PLAU mediates suppressor function through the STAT5 and ERK signaling pathways. Inhibition of the PLAU catalytic domain impairs Treg function, highlighting its role in immune regulation (He2012PLAU).


## References


[1. (Ploug2003StructureFunction) Michael Ploug. Structure-function relationships in the interaction between the urokinase- type plasminogen activator and its receptor. Current Pharmaceutical Design, 9(19):1499–1528, July 2003. URL: http://dx.doi.org/10.2174/1381612033454630, doi:10.2174/1381612033454630. This article has 116 citations and is from a peer-reviewed journal.](https://doi.org/10.2174/1381612033454630)

[2. (Zheng2024PLAU) Yuanliang Zheng, Lixiang Zhang, Kangliang Zhang, Shenghao Wu, Chichao Wang, Risheng Huang, and Hongli Liao. Plau promotes growth and attenuates cisplatin chemosensitivity in arid1a-depleted non-small cell lung cancer through interaction with tm4sf1. Biology Direct, January 2024. URL: http://dx.doi.org/10.1186/s13062-024-00452-7, doi:10.1186/s13062-024-00452-7. This article has 0 citations and is from a peer-reviewed journal.](https://doi.org/10.1186/s13062-024-00452-7)

[3. (Hansen1994Solution) Andrew P. Hansen, Andrew M. Petros, Robert P. Meadows, David G. Nettesheim, Andrew P. Mazar, Edward T. Olejniczak, Robert X. Xu, Terry M. Pederson, Jack Henkin, and Stephen W. Fesik. Solution structure of the amino-terminal fragment of urokinase-type plasminogen activator. Biochemistry, 33(16):4847–4864, April 1994. URL: http://dx.doi.org/10.1021/bi00182a013, doi:10.1021/bi00182a013. This article has 65 citations and is from a peer-reviewed journal.](https://doi.org/10.1021/bi00182a013)

[4. (He2012PLAU) Feng He, Hairong Chen, Michael Probst‐Kepper, Robert Geffers, Serge Eifes, Antonio del Sol, Klaus Schughart, An‐Ping Zeng, and Rudi Balling. Plau inferred from a correlation network is critical for suppressor function of regulatory t cells. Molecular Systems Biology, January 2012. URL: http://dx.doi.org/10.1038/msb.2012.56, doi:10.1038/msb.2012.56. This article has 57 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1038/msb.2012.56)

[5. (Beloglazova2013Structural) I. B. Beloglazova, R. Sh. Beabealashvilli, Ya. G. Gursky, E. V. Bocharov, K. S. Mineev, E. V. Parfenova, and V. A. Tkachuk. Structural investigations of recombinant urokinase growth factor-like domain. Biochemistry (Moscow), 78(5):517–530, May 2013. URL: http://dx.doi.org/10.1134/S0006297913050106, doi:10.1134/s0006297913050106. This article has 10 citations.](https://doi.org/10.1134/S0006297913050106)

[6. (Vincenza2011The) Maria Vincenza Carriero and Maria Patrizia Stoppelli. The urokinase-type plasminogen activator and the generation of inhibitors of urokinase activity and signaling. Current Pharmaceutical Design, 17(19):1944–1961, June 2011. URL: http://dx.doi.org/10.2174/138161211796718143, doi:10.2174/138161211796718143. This article has 55 citations and is from a peer-reviewed journal.](https://doi.org/10.2174/138161211796718143)

[7. (Huai2006Structure) Qing Huai, Andrew P. Mazar, Alice Kuo, Graham C. Parry, David E. Shaw, Jennifer Callahan, Yongdong Li, Cai Yuan, Chuanbing Bian, Liqing Chen, Bruce Furie, Barbara C. Furie, Douglas B. Cines, and Mingdong Huang. Structure of human urokinase plasminogen activator in complex with its receptor. Science, 311(5761):656–659, February 2006. URL: http://dx.doi.org/10.1126/science.1121143, doi:10.1126/science.1121143. This article has 227 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1126/science.1121143)

[8. (Crippa2007Urokinasetype) Massimo P. Crippa. Urokinase-type plasminogen activator. The International Journal of Biochemistry & Cell Biology, 39(4):690–694, 2007. URL: http://dx.doi.org/10.1016/j.biocel.2006.10.008, doi:10.1016/j.biocel.2006.10.008. This article has 92 citations.](https://doi.org/10.1016/j.biocel.2006.10.008)

[9. (Hosen2022Metastatic) S. M. Zahid Hosen, Md. Nazim Uddin, Zhihong Xu, Benjamin J. Buckley, Chamini Perera, Tony C. Y. Pang, Alpha Raj Mekapogu, Mohammad Ali Moni, Faiyaz Notta, Steven Gallinger, Ron Pirola, Jeremy Wilson, Marie Ranson, David Goldstein, and Minoti Apte. Metastatic phenotype and immunosuppressive tumour microenvironment in pancreatic ductal adenocarcinoma: key role of the urokinase plasminogen activator (plau). Frontiers in Immunology, December 2022. URL: http://dx.doi.org/10.3389/fimmu.2022.1060957, doi:10.3389/fimmu.2022.1060957. This article has 19 citations and is from a peer-reviewed journal.](https://doi.org/10.3389/fimmu.2022.1060957)