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Order Sepolyvirales
Published in Paul Pumpens, Peter Pushko, Philippe Le Mercier, Virus-Like Particles, 2022
Paul Pumpens, Peter Pushko, Philippe Le Mercier
The E. coli-driven expression of the MPyV VP1 VLPs for the packaging of DNA was also elaborated (Braun et al. 1999; Henke et al. 2000; Yang and Chen 2000). The specific targeting of the E. coli-produced DNA-packaged MPyV VLPs was achieved by coupling of a recombinant tumor-specific antibody fragment (Stubenrauch et al. 2001; May et al. 2002); addition of a Z domain (Gleiter and Lilie 2001, 2003) or WW domain recognizing proline-rich peptide sequences (Schmidt et al. 2001). Abbing et al. (2004) used the E. coli-produced MPyV VLPs for the encapsulation of proteins (GFP) and low-molecular-mass drugs (methotrexate) via a 49-aa stretch of VP2 as an anchor, either expressed as a fusion protein with GFP or covalently linked to methotrexate. The targeting to the urokinase plasminogen activator receptor was ensured by the insertion of fragments of urokinase plasminogen activator and baculovirus-driven expression of the chimeric DNA-carrying MPyV VLPs (Shin and Folk 2003).
Angiosarcoma
Published in Dongyou Liu, Tumors and Cancers, 2017
In addition, epithelioid angiosarcoma should be distinguished from epithelioid hemangioendothelioma. The former is noted for its greater cellularity, larger cells, more prominent mitotic activity, greater nuclear and nucleolar pleomorphism, and more frequent tightly cohesive cell clusters without a myxohyaline matrix (immunoreactivity for vimentin and cytokeratin). The latter tends to affect younger patients (20–40 years), has an indolent course, and contains specific gene fusion at WWTR1 (WW domain–containing transcription regulator protein 1) and CAMTA1 (calmodulin-binding transcription activator 1) due to the nonrandom reciprocal t(1;3)(p36;q25) translocation, turning the affected endothelial cells to tumors [5]
Primary Eosinophilic Disorders
Published in Richard T. Silver, Ayalew Tefferi, Myeloproliferative Disorders, 2007
Animesh Pardanani, Ayalew Tefferi
Instigated by the serendipitous observation of IM-induced complete hematological remission seen in some patients with both an “HES” phenotype as well as an “SM” phenotype associated with eosinophilia (92,93), in 2003 Cools et al. cloned the FIP1L1-PDGFRA oncogene in such IM-sensitive patients with clonal eosinophilia (21). FIP1L1-PDGFRA is cytogenetically occult and results from an approximately 800 kb interstitial deletion within 4q12 that fuses the 5! portion of FIP1L1 to the 3! portion of PDGFRA (21). Molecular studies showed that the breakpoint in FIP1L1 is relatively promiscuous, while the PDGFRA breakpoint is restricted to exon 12, which encodes part of the protein-protein interaction module with two fully conserved tryptophan (WW domain)-containing juxta-membrane (JM) region (21,33). The mutation results in constitutive activation of PDGFRA, thus providing a molecular explanation for the remarkable efficacy of IM in this disorder (21,92,94,95). Subsequent studies have demonstrated the stem cell origin of the FIP1L1-PDGFRA (96,97), and functional studies have demonstrated transforming properties of the mutation in cell lines and its ability to induce MPD-like phenotype in mice (98,99). Unlike most tyrosine kinase fusion oncogenes, the FIP1L1-encoded sequences are dispensable for cell transformation and there is no requirement for a dimerization motif in FIP1L1-PDGFRA. Instead, disruption of the autoinhibitory JM motif appears to be the basis for constitutive activation of PDGFRA kinase activity (100).
Focusing on Hippo Pathway in Stem Cells of Oral Origin, Enamel Formation and Periodontium Regeneration
Published in Organogenesis, 2022
Tianyi Wang, Kehan Li, Hanghang Liu, En Luo
As shown in Figure 1, the left part is a schematic diagram of the Hippo pathway in Drosophila, while the right part is a corresponding diagram of the Hippo pathway in mammals. The molecule that regulates the Hippo pathway from the start is TAO kinase (TAOK)1/2/3, which phosphorylates MST1 at Thr183 and phosphorylates MST2 at Thr180, thereby activating MST1/2.15,16 In addition to activating downstream LATS1/2 by the C-terminal hydrophobic motif,17 MST1/2 can also phosphorylate Salvador family WW domain‑containing protein 1 (SAV1) and MOB1,18,19 SAV1 can assist the phosphorylation of LATS1/2 by MST1/2 in turn, and phosphorylated MOB1 can combine LATS1/2 as shown in Figure 1.20 Mer in Drosophila has similar functions to mammalian neurofibromatosis type 2 gene (NF2) and can directly bind to LATS1/2.17 Two groups of mitogen-activated protein kinase kinase kinase kinase (MAP4K) can activate LAST1/2 in parallel with MST1/2.21,22 LATS1/2 directly phosphorylates downstream YAP/TAZ by combining with target consensus motifs (HXRXXS).23 Phosphorylation activities inhibit YAP/TAZ from performing its normal function and cannot regulate downstream TEAD1-4.24
Urinary proteomics combined with home blood pressure telemonitoring for health care reform trial: rational and protocol
Published in Blood Pressure, 2021
Lutgarde Thijs, Kei Asayama, Gladys E. Maestre, Tine W. Hansen, Luk Buyse, Dong-Mei Wei, Jesus D. Melgarejo, Jana Brguljan-Hitij, Hao-Min Cheng, Fabio de Souza, Natasza Gilis-Malinowska, Kalina Kawecka-Jaszcz, Carina Mels, Gontse Mokwatsi, Elisabeth S. Muxfeldt, Krzysztof Narkiewicz, Augustine N. Odili, Marek Rajzer, Aletta E. Schutte, Katarzyna Stolarz-Skrzypek, Yi-Wen Tsai, Thomas Vanassche, Raymond Vanholder, Zhen-Yu Zhang, Peter Verhamme, Ruan Kruger, Harald Mischak, Jan A. Staessen
With respect to DVD, the urinary proteome revealed a downregulation of WW domain-binding protein 11 [65]. The WBP-11 gene encodes a nuclear protein, which in cell nuclei co-localises with mRNA splicing factors [76]. In cardiomyocytes, the gene product, WBP-11, interacts with the 52-amino acid integral membrane protein phospholamban (PP-1) and thereby contributes to the regulation of the transmembrane Ca2+ flux via the Ca2+ pump (SERCA), which transports Ca2+ from the cytosol to the sarcoplasmic reticulum. Phosphorylation of PP-1 by protein kinase A and dephosphorylation by WBP-11, respectively, stimulates and inhibits SERCA [77]. Downregulation of WBP-11, as observed in DVD patients, might enhance SERCA activity and impair electromechanical coupling in the myocardium [78].
Targeting PRAS40: a novel therapeutic strategy for human diseases
Published in Journal of Drug Targeting, 2021
Qun Zhou, Shengsong Tang, Xianhui Zhang, Linxi Chen
In 2003, Roth et al. firstly discovered the proline-rich Akt substrate of 40 kD (PRAS40), characterised by a binding protein of 14-3-3 protein and a substrate of protein kinase B (PKB/Akt) [1]. PRAS40, a PKB/Akt substrate induced by insulin, is also known as ‘Akt1s1’, and its phosphorylated protein is identified from nuclear extracts from Hela cells [2]. PRAS40 is characterised by 15% proline at the amino acid ends and is located on human chromosome 19q13.33. These proline-rich regions are potential SH3 and/or WW domain binding partners [3,4]. The sequence of PRAS40 is very similar between humans and other mammals [5]. PRAS40 is expressed in variety of tissues and cells, especially in liver and heart. Studies have shown that the function of PRAS40 is regulated via phosphorylation modification. There are several phosphorylation sites in PRAS40 including Ser183, Ser202, Ser203, Ser212, Ser221, Thr246 and so on [1,3,5–8]. Additionally, PRAS40 phosphorylation site Thr246 induced by Akt, and Ser183, Ser212, Ser221 regulated by mammalian target rapamycin complex 1(mTORC1). PRAS40 is also involved in a variety of physiological and pathophysiological processes such as cell growth, cell apoptosis, oxidative stress, autophagy and angiogenesis. Moreover, PI3K/Akt signalling pathway plays a key regulatory role in these PRAS40-related diseases. PRAS40 is also involved in multiple signalling pathways such as mammalian target rapamycin (mTOR), nuclear factor kappa-B (NF-κB), proto-oncogene serine/threonine-protein kinase PIM-1(PIM1), pyruvate kinase M2(PKM2) etc. Through bioinformatics analysis, it is exhibited that there is also an interaction between PRAS40 and these signalling proteins. Thus, the multiplicity of PRAS40 determines its specific and complex signalling mechanism. Furthermore, PRAS40 is involved in the regulation of multiple diseases. For example, PRAS40 plays a protective role in ischaemia-reperfusion injury and neurodegenerative diseases. Besides, the involvement of miRNAs in regulating PRAS40 has attracted more and more attention, especially in the process of cancer. With its further studies, we believe that PRAS40 can be used as a novel target for disease treatment and drug research.