Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.73 (urokinase-type plasminogen activator)
 10,685 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

HK31 (S565-K595) has previously been shown to encompass the binding domain for plasma prekallikrein (PK) within domain 6 of high molecular weight kininogen (HK). The complementary binding domain for HK within PK is mapped to PK56 (F56-G86), in the Apple 1 domain and to PK266 (K266-C295) in the Apple 4 domain. Isothermal titration calorimetry demonstrated that either PK peptide binds to HK31 in 1:1 stoichiometry. Binding of the alternate PK peptide into a ternary complex is facilitated nearly 2-fold. Fluorescence emission spectroscopy revealed that only the binding of PK56 caused a limited decrease in intrinsic tryptophane fluorescence emission intensity of HK31. We conclude that the two PK peptides bind to the HK peptide at different sites. To map the minimal sequence within HK31, truncated new peptides were tested for their ability to compete with HK for binding PK in a cell-free system. D567-T591, a 25-residue peptide which contains sufficient structural information for binding kallikrein in solution, blocked the binding of kallikrein to HK bound to endothelial cells and inhibited PK activation to kallikrein and the generation of kallikrein-activated urokinase on endothelial cell surfaces. HK-derived peptides could modulate excessive fibrinolysis and hypotension in sepsis and multiple trauma.
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PMID:Physical and biological significance of peptide sequences mediating the interaction between high molecular weight kininogen and plasma prekallikrein. 922 46

Background: Recent discovery of gene rearrangements have brought a new look to the molecular pathogenesis of cancer. Gene fusions occur in nearly 60% of prostate adenocarcinoma, being the TMPRSS2-ERG one of the most common. Evidence supports the role of ERG fusion in tumorigenesis, progression and invasion via effecting pathways such as WNT, MYC, uPA, PI3K/AKT/PTEN, RAS/RAF/MAPF, NKX3.1, GST-pi and androgen receptor (AR) mediated signaling. Most of the ERG fusions involve 5'-partners androgen responsive. Therefore, we aimed to evaluate AR and ERG fusion protein expression on prostate tissue to find clinicopathological applications and possible role in therapy. Methods: One hundred three samples, including prostate core biopsies and radical prostatectomy specimens, were evaluated for ERG and AR expression by immunohistochemistry (IHC). ERG rearrangement was done by fluorescence in situ hybridization (FISH) on 11 randomly selected cases and correlated with IHC results. Results: From the total of 103 samples, eight (8/103) were benign, fourteen (14/103) had atypical glands, two (2/103) had prostatic intraepithelial neoplasia (PIN), and seventy nine (79/103) showed prostate adenocarcinoma. Forty four (44/79) tumor cases were Gleason score (GS) 6-7 (lower GS), and thirty five (35/79) were GS of 8-10 (higher GS). ERG immunoreaction was observed in 27.8% (22/79) of the tumor cases, showing higher expression in those with lower GS (68.2%, 15/22) compared to higher GS (31.8%, 7/22). Neither benign glands nor PIN stained with ERG. AR expression was observed in 75% of benign samples, 78.5% of atypical glands, 100% of PIN, and in 87.3% of tumor cases with no significant difference based on GS. Co-expression of ERG and AR was evaluated on all the tumor samples. ERG+/AR+ was seen in 77.3% (17/22) of the ERG+ tumor cases, with higher frequency in lower GS (64.7%, 11/17) compared to those with higher GS (35.3%, 6/17). All but five corresponding ERG+ tumor samples were negative for AR. Only 5 samples were ERG-/AR- corresponding to adenocarcinoma GS of 6. Presence or absence of ERG rearrangement was confirmed by FISH and correlated with IHC results. Conclusions: Characterization of ERG status by IHC in prostate tissue has an excellent correlation with FISH. It may also assist in diagnosis since none of the benign glands stained with ERG. Co-expression of ERG+/AR+ in prostate tumor by IHC may suggest gene fusion between ERG and a 5'-partner driven by androgen signaling such as TMPRSS2, which it could represent an important ancillary test for clinical management and development of new therapeutic targets.
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PMID:Correlation between ERG Fusion Protein and Androgen Receptor Expression by Immunohistochemistry in Prostate, Possible Role in Diagnosis and Therapy. 2890 Apr 98