scholarly journals Kringle Domain

2020 ◽  
Author(s):  
Keyword(s):  
Kringle Domain

Enhancement of anti-tumor activity by low-dose combination of the recombinant urokinase kringle domain and celecoxib in a glioma model

2010 ◽  
Vol 288 (2) ◽  
pp. 251-260 ◽  
Author(s):  
Chung Kwon Kim ◽  
Young Ae Joe ◽  
Suk-Keun Lee ◽  
Eun-Kyoung Kim ◽  
Eunju O ◽  
...  
Keyword(s):  
Low Dose ◽  
Kringle Domain ◽  
Dose Combination ◽  
Glioma Model ◽  
Anti Tumor Activity

Crystal Structure of the Interaction of Human Urokinase Plasminogen Activitor with Its Receptor.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 683-683 ◽  
Author(s):  
Qing Huai ◽  
Andrew P. Mazar ◽  
Graham Parry ◽  
Alice Kuo ◽  
Douglas B. Cines ◽  
...  
Keyword(s):  
Ternary Complex ◽  
Hydrophobic Interactions ◽  
Structural Basis ◽  
Diffusion Method ◽  
Monoclinic Space Group ◽  
Fab Fragment ◽  
Data Set ◽  
Kringle Domain ◽  
Amino Terminal ◽  
High Affinity

Abstract Urokinase-type plasminogen activator (uPA) and its cellular receptor (uPAR) mediate plasminogen activation. The uPA binds to uPAR with high affinity (Kd 0.1–1nM), thus localizing the generation of plasmin from plasminogen on the surface of a variety of cells. uPA-uPAR binding is also involved in other cellular functions and diverse pathophysiological processes such as tissue remodeling during wound healing, atherosclerosis, angiogenesis and tumor metastasis. We have determined the structure of uPAR complexed with the amino terminal fragment (amino acid residues 1–143) of uPA (ATF), which contains the uPAR binding domain, at 1.9 Å resolution by X-ray crystallography. Soluble uPAR (suPAR) and the ATF were expressed separately in stably transfected Drosophila Schneider 2 (S2) cells. The suPAR-ATF complex was crystallized by the sitting-drop vapor diffusion method. However, the diffraction of this crystal was limited to 3.1 Å resolution. Therefore, the Fab fragment of an antibody raised against suPAR, ATN-615, was used to facilitate suPAR-ATF crystallization. Crystals of the suPAR-ATF-ATN615 ternary complex were generated by microdialysis with 4% PEG4K, 5% ethylene glycol, 5% methanol, 0.05% sodium azide, 50 mM cacodylate pH 6.5. A complete data set of the ternary complex to 1.9 Å was collected using synchrotron radiation at the Advanced Photon Source (APS), Argonne National Laboratory. The crystals belong to the monoclinic space group, with unit cell parameters a=51.79 Å, b=86.81 Å, c=124.69 Å and β=94.54°. uPAR is comprised of three consecutive domains (D1, D2 and D3) that form the shape of a thick-walled teacup with a diameter of about 52 Å and a height of 27 Å. At the center of teacup and surrounded by three suPAR domains is a cone shape cavity with a wide opening (25 Å) and large depth (14 Å). ATF consists of a growth factor domain (GFD) and a kringle domain. Both domains pack more tightly in the complex structure compared with their unbound state. The GFD domain of uPA occupies part of the uPAR cavity and is primarily responsible for uPAR binding. The D1 domain of uPAR forms three hydrogen bonds and many hydrophobic interactions with the GFD domain of uPA, thus playing an important role in the binding of uPA. However, D2 and D3 of uPAR also have direct interactions with the GFD domain of uPA. The kringle domain of uPA sits outside the uPAR pocket, but forms some direct contacts with the D1 domain of uPAR. Therefore, the three domains of uPAR and two domains of uPA form a complementary interaction, which describes the structural basis for the high affinity binding of uPA to uPAR. This structure presents the first high resolution view of uPA-uPAR interaction, and may provide a new platform to design de novo uPA-uPAR antagonists.

Multiple Myeloma Plasma Cell Expression of Hepatocyte Growth Factor mRNA Isoforms Correlates with Overall Survival In Myeloma Patients

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4983-4983
Author(s):  
Ida Bruun Kristensen ◽  
Jacob Haaber Christensen ◽  
Maria Lyng ◽  
Tobias W Klausen ◽  
Lene Meldgaard Knudsen ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Growth Factor ◽  
Prognostic Factor ◽  
Hepatocyte Growth Factor ◽  
Full Length ◽  
Transcript Variant ◽  
Kringle Domain ◽  
Adverse Prognostic Factor ◽  
Hepatocyte Growth

Abstract Abstract 4983 Background: Full length Hepatocyte growth Factor (HGF) (consisting of four “kringle”-domains) is known to be produced by multiple myeloma plasma cells (MM PC) in vivo and HGF is among the 70 most up regulated genes in MM. Elevated serum levels of HGF are known to be an adverse prognostic factor and recently, MM PC expression of the HGF receptor cMET has been shown to be an adverse prognostic factor. Functionally, HGF inhibits osteoblastogenesis in vitro and promotes migration of MM PC. So far, studies on HGF and its impact in MM have focused on measuring full-length or all isoforms of HGF expression. However, naturally occurring shorter isoforms of HGF (known as NK1 and NK2) are known to work as partial inhibitors of full-length HGF (Otsuka et al, Mol and Cell Biol, 2000). We examined the HGF isoforms and cMET expression at the mRNA level in isolated MM PC of >150 newly diagnosed patients with MM, 18 MGUS patients and 8 healthy volunteers (HV) and associated it to overall survival (OS) and degree of osteolytic bone disease (OBD). Methods: Aberrant MM PCs (CD38++/CD19-/CD45-/i/CD56-/+/++) were sorted directly into PCR tubes by fluorescence activated cell sorting (FACS) using a FACS Aria (BDIS). In all cases a PC-purity above 98% was obtained. A cDNA archive was generated by global reverse transcription. By using a polyadenylating step 5x-oligo(dT)-transcript-poly(A)-3xcDNA were generated and finally amplified by PCR using a sequence independent X-(dT)24 primer. The conditions of the reverse transcriptase reaction is designed to limit the size of the first strand cDNA to 300–700 bases, which leads to a more uniform and unbiased amplification. Isoform specific primers were designed using the Primer Express program and experimentally tested. The HGF version covered full-length HGF (transcript variant 1 and 3), HGF2 covered the 2 kringle domain versions (transcript variant 2 and 4) and HGF5 covered the 1 kringle domain version (transcript variant 5). cMET only exists in one isoform. Quantitative PCR was performed using β-actin as internal reference gene, using the δCt method. Determination of positivity or negativity was made from a cut-off-value at 10E-05. OBD was evaluated by standard radiographic methods. The MM patients were treated with either high-dose melphalan with ASCT or melphalan-prednisone according to age recommendations. Results: At least one of the HGF isoforms were found to be expressed in PCxs from 43% of MM patients compared to 32% of MGUS patients, and 0% of HV. Full length HGF was expressed in 17 %, HGF2 in 29%, and HGF5 in 26% of the MM patients. Expression of any HGF variant was associated to an adverse OS (p=0.04) (Fig. 1). The quantitative expression of the transcript variant 5 associated negatively to OS (p=0.02), while expression of the other specific isoforms showed no association to OS. Thus, somehow surprisingly, MM PC expression of the shorter isoform of HGF (HGF5) was more predictive of poor prognosis. A tendency towards elevated expression of full-length HGF in patients with no OBD compared to limited or advanced was observed but did not reach statistically significance (p=0.13). Pre-liminary analysis of cMET expression data showed no correlation between MM PC cMet expression and degree of OBD. Further data on cMet will be presented at the meeting. Disclosures: No relevant conflicts of interest to declare.

The recombinant kringle domain of urokinase plasminogen activator inhibits in vivo malignant glioma growth

2007 ◽  
Vol 98 (2) ◽  
pp. 253-258 ◽  
Author(s):  
Chung Kwon Kim ◽  
Sung Hee Hong ◽  
Young Ae Joe ◽  
Byoung-Shik Shim ◽  
Suk-Keun Lee ◽  
...  
Keyword(s):  
Malignant Glioma ◽  
Plasminogen Activator ◽  
Urokinase Plasminogen Activator ◽  
Kringle Domain ◽  
Glioma Growth
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