# KNG1

## Overview
Kininogen 1 (KNG1) is a gene that encodes for the protein kininogen 1, a key component in the kallikrein-kinin system, which is crucial for regulating blood coagulation, inflammation, and blood pressure. The protein itself is a precursor to kinins, particularly bradykinin, which are involved in vasodilation and inflammatory responses. Kininogen 1 is not only essential for the intrinsic pathway of blood coagulation but also plays a significant role in the innate immune response by contributing to the production of antimicrobial peptides. Additionally, it interacts with various signaling pathways influencing cell proliferation, survival, and angiogenesis, highlighting its multifaceted role in both physiological and pathological processes (Cagliani2013Evolutionary; Sabater-Lleal2012A; Xu2018Overexpression).

## Function
Kininogen 1 (KNG1) is a multifunctional protein that plays a pivotal role in several critical physiological processes, including blood coagulation, inflammation, and the innate immune response. KNG1 is a precursor to kinins, particularly bradykinin, which are involved in mediating vascular permeability, inducing hypotension, and promoting inflammation. The protein is cleaved by kallikrein to release these kinins, which are potent vasodilators (Cagliani2013Evolutionary; Liu2016Serum).

In the context of blood coagulation, KNG1 is essential for the intrinsic pathway, which is crucial for the formation of a fibrin clot to limit blood loss from damaged vessels. It acts as a cofactor in the activation of kallikrein and factor XII, initiating the contact pathway of blood coagulation (Martin-Fernandez2017Next; Sabater-Lleal2012A). Additionally, KNG1 is involved in the immune response by its proteolysis resulting in the generation of antimicrobial peptides (AMPs) that target a broad spectrum of pathogens, enhancing the body's defense mechanisms (Cagliani2013Evolutionary).

Furthermore, KNG1 influences various signaling pathways that affect cell proliferation, survival, and angiogenesis. It is significantly involved in the PI3K/AKT signaling pathway, which is crucial for these cellular processes. The protein's role extends to influencing the expression and function of other proteins within the contact pathway, such as prekallikrein and factor XI, thereby modulating blood coagulation and inflammatory responses (Sabater-Lleal2012A; Xu2018Overexpression).

## Clinical Significance
KNG1 (kininogen 1) mutations and expression alterations are implicated in various vascular and thrombotic conditions, significantly impacting human health. The SNP rs710446 in the KNG1 gene, specifically the Ile581Thr variant, is associated with an increased risk of venous thrombosis (VT). This association is evidenced by the higher frequency of the rs710446-C allele in patients with VT compared to healthy controls, and its linkage with increased odds of developing VT (Morange2011KNG1). Additionally, this SNP is linked to altered activated partial thromboplastin time (aPTT), a critical measure in coagulation assessments, further underscoring its clinical relevance in thrombotic diseases (Sabater-Lleal2012A).

Beyond thrombosis, KNG1 gene alterations are also associated with increased susceptibility to ischemic stroke (IS). Specific variants like rs710446 have been identified as significant contributors to IS risk, particularly through gene-gene interactions that potentiate this risk (Hu2015Variants). The gene's role in vascular disease or remodeling is further highlighted by its implication in conditions such as in-stent restenosis post-angioplasty and its potential involvement in early atherosclerotic processes (Hu2015Variants).

In cancer, KNG1 has been identified as a potential serum biomarker for the early detection of colorectal cancer (CRC), with its expression levels varying significantly between preoperative and postoperative states in CRC patients (Quesada-Calvo2017OLFM4). This suggests that KNG1 could play a role in tumor biology, possibly through its antiangiogenic properties and effects on cell proliferation.

## Interactions
Kininogen 1 (KNG1) is involved in several physical interactions with other proteins, primarily through its role in the kallikrein-kinin system. KNG1 interacts with prekallikrein and factor XI, which are crucial for the activation of the kallikrein-kinin system, influencing blood coagulation and inflammatory responses. In the context of essential hypertension, KNG1 has been identified as a hub protein with extensive connectivity in protein-protein interaction networks, suggesting its involvement in multiple signaling pathways related to blood pressure regulation (Ran2013Construction). Specifically, KNG1 activates the G protein-coupled receptors B2R and B1R through its interaction with the NOS3 protein, playing a significant role in vasodilation and blood pressure regulation (Ran2013Construction).

In cancer research, particularly glioma, KNG1 overexpression has been shown to interact with various signaling pathways. It affects the PI3K/Akt pathway, leading to changes in cell viability, apoptosis, and angiogenesis. This interaction involves the modulation of key proteins such as VEGF, CyclinD1, and caspase-3, indicating a role in tumor suppression (Xu2018Overexpression). These interactions highlight the multifaceted roles of KNG1 in both physiological and pathological processes.


## References


[1. (Martin-Fernandez2017Next) Laura Martin-Fernandez, Giovana Gavidia-Bovadilla, Irene Corrales, Helena Brunel, Lorena Ramírez, Sonia López, Juan Carlos Souto, Francisco Vidal, and José Manuel Soria. Next generation sequencing to dissect the genetic architecture of kng1 and f11 loci using factor xi levels as an intermediate phenotype of thrombosis. PLOS ONE, 12(4):e0176301, April 2017. URL: http://dx.doi.org/10.1371/journal.pone.0176301, doi:10.1371/journal.pone.0176301. (8 citations) 10.1371/journal.pone.0176301](https://doi.org/10.1371/journal.pone.0176301)

[2. (Xu2018Overexpression) Jinfang Xu, Jun Fang, Zhonghao Cheng, Longlong Fan, Weiwei Hu, Feng Zhou, and Hong Shen. Overexpression of the kininogen-1 inhibits proliferation and induces apoptosis of glioma cells. Journal of Experimental & Clinical Cancer Research, August 2018. URL: http://dx.doi.org/10.1186/s13046-018-0833-0, doi:10.1186/s13046-018-0833-0. (54 citations) 10.1186/s13046-018-0833-0](https://doi.org/10.1186/s13046-018-0833-0)

[3. (Ran2013Construction) Jihua Ran, Hui Li, Jianfeng Fu, Ling Liu, Yanchao Xing, Xiumei Li, Hongming Shen, Yan Chen, Xiaofang Jiang, Yan Li, and Huiwu Li. Construction and analysis of the protein-protein interaction network related to essential hypertension. BMC Systems Biology, April 2013. URL: http://dx.doi.org/10.1186/1752-0509-7-32, doi:10.1186/1752-0509-7-32. (64 citations) 10.1186/1752-0509-7-32](https://doi.org/10.1186/1752-0509-7-32)

[4. (Morange2011KNG1) Pierre-Emmanuel Morange, Tiphaine Oudot-Mellakh, William Cohen, Marine Germain, Noémie Saut, Guillemette Antoni, Marie-Christine Alessi, Marion Bertrand, Anne-Marie Dupuy, Luc Letenneur, Mark Lathrop, Lorna M. Lopez, Jean-Charles Lambert, Joseph Emmerich, Philippe Amouyel, and David-Alexandre Trégouët. Kng1 ile581thr and susceptibility to venous thrombosis. Blood, 117(13):3692–3694, March 2011. URL: http://dx.doi.org/10.1182/blood-2010-11-319053, doi:10.1182/blood-2010-11-319053. (50 citations) 10.1182/blood-2010-11-319053](https://doi.org/10.1182/blood-2010-11-319053)

[5. (Liu2016Serum) Changming Liu, Liangen Mao, Zepeng Ping, Tingting Jiang, Chong Wang, Zhongliang Chen, Zhongjie Li, and Jicheng Li. Serum protein kng1, apoc3, and pon1 as potential biomarkers for yin-deficiency-heat syndrome. Evidence-Based Complementary and Alternative Medicine, 2016:1–13, 2016. URL: http://dx.doi.org/10.1155/2016/5176731, doi:10.1155/2016/5176731. (15 citations) 10.1155/2016/5176731](https://doi.org/10.1155/2016/5176731)

[6. (Sabater-Lleal2012A) Maria Sabater-Lleal, Angel Martinez-Perez, Alfonso Buil, Lasse Folkersen, Juan Carlos Souto, Maria Bruzelius, Montserrat Borrell, Jacob Odeberg, Angela Silveira, Per Eriksson, Laura Almasy, Anders Hamsten, and José Manuel Soria. A genome-wide association study identifies kng1 as a genetic determinant of plasma factor xi level and activated partial thromboplastin time. Arteriosclerosis, Thrombosis, and Vascular Biology, 32(8):2008–2016, August 2012. URL: http://dx.doi.org/10.1161/atvbaha.112.248492, doi:10.1161/atvbaha.112.248492. (51 citations) 10.1161/atvbaha.112.248492](https://doi.org/10.1161/atvbaha.112.248492)

[7. (Hu2015Variants) Zhongyang Hu, Jia Liu, Zhi Song, Qiao Hou, Xuejun Fan, and Deren Hou. Variants in the atherogenic alox5ap, thbd, and kng1 genes potentiate the risk of ischemic stroke via a genetic main effect and epistatic interactions in a chinese population. Journal of Stroke and Cerebrovascular Diseases, 24(9):2060–2068, September 2015. URL: http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2015.04.036, doi:10.1016/j.jstrokecerebrovasdis.2015.04.036. (15 citations) 10.1016/j.jstrokecerebrovasdis.2015.04.036](https://doi.org/10.1016/j.jstrokecerebrovasdis.2015.04.036)

[8. (Cagliani2013Evolutionary) Rachele Cagliani, Diego Forni, Stefania Riva, Uberto Pozzoli, Marta Colleoni, Nereo Bresolin, Mario Clerici, and Manuela Sironi. Evolutionary analysis of the contact system indicates that kininogen evolved adaptively in mammals and in human populations. Molecular Biology and Evolution, 30(6):1397–1408, March 2013. URL: http://dx.doi.org/10.1093/molbev/mst054, doi:10.1093/molbev/mst054. (23 citations) 10.1093/molbev/mst054](https://doi.org/10.1093/molbev/mst054)

[9. (Quesada-Calvo2017OLFM4) Florence Quesada-Calvo, Charlotte Massot, Virginie Bertrand, Rémi Longuespée, Noëlla Blétard, Joan Somja, Gabriel Mazzucchelli, Nicolas Smargiasso, Dominique Baiwir, Marie-Claire De Pauw-Gillet, Philippe Delvenne, Michel Malaise, Carla Coimbra Marques, Marc Polus, Edwin De Pauw, Marie-Alice Meuwis, and Edouard Louis. Olfm4, kng1 and sec24c identified by proteomics and immunohistochemistry as potential markers of early colorectal cancer stages. Clinical Proteomics, March 2017. URL: http://dx.doi.org/10.1186/s12014-017-9143-3, doi:10.1186/s12014-017-9143-3. (62 citations) 10.1186/s12014-017-9143-3](https://doi.org/10.1186/s12014-017-9143-3)