Disease relevance of KNG1

• High molecular weight kininogen (HK) is a plasma protein that is cleaved by plasma kallikrein in the clinical settings of sepsis and chronic inflammatory diseases such as rheumatoid arthritis and Crohn's disease [1].
• Domain 5 of kininogen inhibits proliferation of human colon cancer cell line (HCT-116) by interfering with G1/S in the cell cycle [2].
• Effect of His-Gly-Lys motif derived from domain 5 of high molecular weight kininogen on suppression of cancer metastasis both in vitro and in vivo [3].
• The cDNA insert of one of these phage was sequenced and shown to code for alpha 2-thiol proteinase inhibitor as identified by a partial amino acid sequence of the light chain of alpha 2-thiol proteinase inhibitor [4].
• We found that human kinin-free high-molecular-weight kininogen (kf-HK) significantly inhibited vitronectin-mediated migration (haptotaxis) and invasive potentiation (haptoinvasion) of osteosarcoma (MG-63) cells but that HK, LK, the common heavy chain of HK and LK, and the light chain (D6(H)) of HK had no inhibitory effect [5].

High impact information on KNG1

• The importance of the tissue kallikrein system depends upon secretion of the active form of the requisite enzyme in the presence of a source of kininogen [6].
• Since tissue kallikreins are widely distributed in tissues, and since lymph and interstitial fluid contains kininogen (271), a local milieu for potential kinin formation is always present [6].
• Substance P precursor and kininogen: their structures, gene organizations, and regulation [7].
• Consumption of high-molecular-weight kininogen in hereditary angioedema [8].
• Prothrombin times, thrombin times, platelet-function tests and the levels of factors XII, XI, IX, VIII, prekallikrein and high-molecular-weight kininogen were normal [9].

Chemical compound and disease context of KNG1

• It may also explain hypotension, by release of bradykinin from high molecular weight kininogen, and complement activation, by activated factor XII, that has been demonstrated in these patients [10].
• Complexes between C1-inhibitor, kallikrein, high molecular weight kininogen, plasma thromboplastin antecedent, and plasmin in normal human plasma and hereditary angioneurotic edema plasmas containing dysmorphic C1-inhibitors: role of cold activation [11].
• Thus, LPS and lipid A of E coli and peptidoglycan and teichoic acid of S aureus can generate kallikrein amidolytic activity in a mixture of purified factor XII, prekallikrein, and high-Mr kininogen [12].
• We observed higher titers of Hageman factor, prolactin, and high molecular weight kininogen but no significant change in estradiol or prekallikrein in survivors of myocardial infarction compared with controls [13].
• We earlier reported the IgE-mediated release of a basophil kallikrein of anaphylaxis (BK-A) which, like plasma kallikrein, is an arginine esterase and cleaves human plasma kininogen generating immunoreactive kinin [14].

Biological context of KNG1

• Kininogen therefore is a critical factor required for the functioning of Hageman factor-dependent coagulation and fibrinolysis and for the activation of prekallikrein [15].
• These investigations identify a new function for cytokeratin 1 as a kininogen binding protein [16].
• Mapping of the discontinuous H-kininogen binding site of plasma prekallikrein. Evidence for a critical role of apple domain-2 [17].
• The first and the last half-cystine residues of the amino acid sequence form a disulphide loop which spans the heavy- and the light-chain portion of the kininogen molecule [18].
• Induction of apoptosis in vascular cells by plasminogen activator inhibitor-1 and high molecular weight kininogen correlates with their anti-adhesive properties [19].

Anatomical context of KNG1

• A kininogen binding protein(s), a putative receptor, was identified on endothelial cells [16].
• High molecular weight kininogen and factor XII binding to endothelial cells and astrocytes [20].
• The aim of this work was to determine the effect of kininogen degradation by human neutrophil elastase (HNE) on kinin generation by tissue and plasma kallikreins [21].
• High (H) and low (L) molecular weight kininogen, plasma prekallikrein and plasma kallikrein were detected by Western blot analysis in human term placenta and in maternal and fetal blood, whereas tissue kallikrein was not [22].
• The co-localization of kininogen and plasma prekallikrein/plasma kallikrein suggests that kinins could be generated locally in placental capillaries [22].

Associations of KNG1 with chemical compounds

• A 54-kDa protein was isolated by a biotin-high molecular mass kininogen (HK) affinity column that, on aminoterminal sequencing of tryptic digests, was identified as cytokeratin 1 [16].
• Proteolytic cleavage of single-chain high molecular weight kininogen (HK) by kallikrein releases the short-lived vasodilator bradykinin and leaves behind 2-chain high molecular weight kininogen (HKa) that has been previously reported to exert antiadhesive properties as well as to bind to the urokinase receptor (uPAR) on endothelial cells [23].
• Different mechanisms define the antiadhesive function of high molecular weight kininogen in integrin- and urokinase receptor-dependent interactions [23].
• High molecular weight kininogen regulates platelet-leukocyte interactions by bridging Mac-1 and glycoprotein Ib [24].
• Low-Mr kininogen contains 18 half-cystine residues forming nine disulphide bridges [18].

Physical interactions of KNG1

• High molecular weight kininogen (HK) was previously shown to interact with both GPIbalpha and Mac-1 through its domains 3 and 5, respectively [24].
• We conclude residues Lys244-Pro254 on kininogen heavy chain is responsible for binding to thrombospondin on the surface of activated platelets [25].
• T-kininogen did not release any immunoreactive kinins when complexed with cathepsin L, as previously observed using tissue kallikreins [26].
• The purified light chain derived from kinin-free HMW-kininogen is shown to compete with native MHW-kininogen for binding to Hageman factor substrates and direct binding of the isolated light chain to prekalikrein and Factor XI is demonstrated [27].
• The region Gly-486-Lys-502 from the carboxyl terminus of the domain 5 was identified as responsible for inhibition of the VN-alpha(IIb)beta(3)-integrin interaction, as this portion was also found to mediate kininogen binding to VN [28].

Enzymatic interactions of KNG1

• Tissue kallikrein is a serine proteinase which is capable of cleaving kininogen substrate to release the vasoactive kinin peptide [29].
• Furthermore, peptide RPPGF or high-molecular-weight kininogen prevented alpha-thrombin from cleaving the thrombin receptor peptide, NATLDPRSFLLR, between arginine and serine [30].
• Although at a drastically reduced rate, high molecular weight kininogen was cleaved by alpha 2M-bound kallikrein [31].
• Tryptase from human mast cells has been shown (in vitro) to catalyze the destruction of fibrinogen and high-molecular-weight kininogen as well as the activation of C3a and collagenase [32].
• At pH 7.35, high molecular weight kininogen is slightly cleaved by cathepsin B into fragments of 60 kDa, and cathepsin B kininogenase activity is impaired [33].

Co-localisations of KNG1

• B2 receptor mRNA was colocalized with kininogen mRNA in the kidney except the podocytes [34].

Regulatory relationships of KNG1

• High-Molecular-Weight Kininogen Fragments Stimulate the Secretion of Cytokines and Chemokines Through uPAR, Mac-1, and gC1qR in Monocytes [35].
• In this study we show that the human kininogen gene is strongly up-regulated by agonists of the farnesoid X receptor (FXR), a nuclear receptor for bile acids [36].
• INTRODUCTION: Preliminary studies have shown that high molecular mass kininogen (HK) inhibits cathepsin G-induced platelet activation [37].
• High molecular weight kininogen (HK) also stimulates the expression of cell surface plasminogen activator activity through its ability to serve as an acquired receptor for prekallikrein, which, after its activation, may directly activate prourokinase [38].
• Evidence for binding of the ectodomain of amyloid precursor protein 695 and activated high molecular weight kininogen [39].

Other interactions of KNG1

• Williams trait. Human kininogen deficiency with diminished levels of plasminogen proactivator and prekallikrein associated with abnormalities of the Hageman factor-dependent pathways [15].
• Plasma prekallikrein, a zymogen of the contact phase system, circulates in plasma as heterodimeric complex with H-kininogen [17].
• Although both cathepsins processed high-molecular weight kininogen under stoichiometric conditions, only cathepsin L generated significant amounts of immunoreactive kinins [40].
• We show that the digestion of both low molecular mass (LK) and high molecular mass (HK) forms of human kininogen by HNE renders them essentially unsusceptible to processing by human urinary kallikrein (tissue-type) and also significantly quenches the kinin release from HK by plasma kallikrein [21].
• Plasminogen activator inhibitor-1 (PAI-1) and two-chain high molecular weight kininogen (HKa) exert anti-adhesive properties in vitronectin-dependent cell adhesion [19].

Analytical, diagnostic and therapeutic context of KNG1

• When normal plasma was fractionated to identify the factor that corrects all the abnormalities in Williams trait plasma, the Williams factor was identified as a form of kininogen by its behavior on ion exchange chromatography, gel filtration, disc gel electrophoresis, and elution from an anti-low molecular weight kininogen immunoadsorbent [15].
• Isothermal titration calorimetry was used to assess binding between the kallikrein-based peptides and a peptide encompassing the kallikrein binding domain in kininogen (Ser565-Lys595) [41].
• A Northern blot showed that the expression of LMW kininogen is in the liver and the kidney [34].
• To understand the function of kinin in the kidney, we have identified the cellular localization of the human low-molecular-weight (LMW) kininogen and bradykinin B2 receptor mRNAs in the human kidney by in situ hybridization histochemistry [34].
• Using antisera monospecific to high molecular weight kininogen, a competitive enzyme-linked immunosorbent assay (CELISA) was developed to directly measure platelet high-molecular weight kininogen [42].

References