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Gene Expression and Function of the Cellular Receptor for u-PA (u-PAR)
Published in Pia Glas-Greenwalt, Fibrinolysis in Disease Molecular and Hemovascular Aspects of Fibrinolysis, 2019
Vincent Ellis, Michael Ploug, Torben Plesner, Keld Danø
Plasminogen activation, catalyzed by the serine proteases u-PA (urokinase-type plasminogen activator) and t-PA (tissue plasminogen activator), is thought to play an important role in a variety of physiological and pathological processes. These include fibrinolysis and the degradation of extracellular matrix necessary for cellular invasion, migration, and tissue remodeling. The two plasminogen activators differ primarily in the domain organization of their noncatalytic regions, which regulate the function of the two plasminogen activators by binding to various “cofactor” molecules in a manner suggesting that they play quite different biological roles. Thus determinants within the “finger” and “kringle” domains of t-PA allow its binding to fibrin, whereas the epidermal growth factor-like domain (GFD) of u-PA enables it to bind to a specific cell surface receptor molecule. Therefore, although both plasminogen activators have the same specificity (generating plasmin by cleavage of a single Arg-Val bond), t-PA is thought to be primarily involved in the maintenance of hemostasis through the dissolution of fibrin, while u-PA is thought to be involved in generating the pericellular proteolytic activity needed for degradation of extracellular matrix, basement membranes, and other structural barriers during cellular migration and invasion.
Cellular Trafficking
Published in Martin Berry, Ann Logan, CNS Injuries: Cellular Responses and Pharmacological Strategies, 2019
The term selectin was introduced to describe three adhesion molecules whose function and expression were highly selective and which possessed a terminal lectin domain. The nomenclature for each molecule relates to the cell on which they were first described: E-selectin (endothelium), L-selectin (lymphocyte), and P-selectin (platelet). All three share similar structural features: (1) an extracellular amino terminal carbohydrate-binding (i.e., lectin-like) domain that requires Ca2+ for activation; (2) an epidermal growth factor-like domain; and (3) repeated domains with homologies to complement-regulatory proteins.
Endothelial Cells
Published in John H. Barker, Gary L. Anderson, Michael D. Menger, Clinically Applied Microcirculation Research, 2019
Three members of the selectin family currently exist: L-selectin (LEC-CAM-1, LAM-1, Leu 8, and TQ-1), E-selectin (LEC-CAM-2, ELAM-1, endothelial-leukocyte adhesion molecule), and P-selectin (LEC-CAM-3 PADGEM, platelet-activation-dependent-granulocyte-external-membrane protein, GMP-140, CD62).68–73 L-selectin is confined to leukocytes and is involved in leukocyte homing. E-selectin is found on ECs, and P-selectin is found on both ECs and platelets. These molecules are transmembrane glycoproteins that contain an amino-terminal lectin domain, followed by an epidermal growth factor-like domain, and a varying number of complement-like consensus repeats. P- and E-selectin bind sialyated Lewis X (SleX) carbohydrates, which are commonly found on glycoproteins and glycolipids of myeloid cells. The natural ligand for L-selectin remains elusive.
The significance of the neuregulin-1/ErbB signaling pathway and its effect on Sox10 expression in the development of terminally differentiated Schwann cells in vitro
Published in International Journal of Neuroscience, 2021
Xizhong Yang, Cuijie Ji, Xinyue Liu, Chaoqun Zheng, Yanxin Zhang, Ruowu Shen, Zangong Zhou
Neuregulin-1 (NRG-1) is a member of the family of regulatory proteins that contain the EGF (epidermal growth factor)-like domain. It is a type of transmembrane protein that regulates the growth and development of glial cells and neurons [8]. The functional receptor of NRG is the ErbB receptor, which includes ErbB2/HER2, ErbB3/HER3, and ErbB4/HER4. ErbB is a member of the EGF receptor family of transmembrane tyrosine kinases. Both ErbB2 and ErbB3 receptors are required in the development of SCs, but these two receptors have different effects; ErbB3 can bind with extracellular ligands with high affinity even though it is inactive, while ErbB2 tyrosine kinase activity can activate downstream signaling [9]. Sox10 belongs to the Sox family, members of which contain a DNA binding domain that is similar to the HMG (high mobility group) domain of the SRY transcription factor family [10]. The structure of Sox10 is highly conserved, especially the structure of its functional domains, such as the N-terminal to C-terminal dimerization domain, the HMG domain, and the protein interaction (K2) domain [11]. The Sox gene family is involved in stem cell maintenance, cell differentiation and tissue formation. Sox10 plays an important role in the formation of the neural crest and peripheral nervous system, the maturation and terminal differentiation of SCs, and the differentiation of melanocytes. Sox10 and Oct6 have synergistic effects on the differentiation and development of SCs [12]. In addition, in the central nervous system and the peripheral nervous system, Sox10 is highly expressed in neural crest cells and glial cells.
Association between circulating microRNA-126 expression level and tumour necrosis factor alpha in healthy smokers
Published in Biomarkers, 2019
Asmaa M. Elfiky, Asmaa Ahmed Mahmoud, Hala M. Zeidan, Mohamed Mostafa Soliman
MiR-126 is not only a clinical marker that reflects the incidence of malignancies, but it is a regulatory factor in development tumourigenesis and metastases, as well (Sun et al. 2010, Song et al. 2016). In SCLC, more than 95% of patients have a smoking history and their 5-year survival rates are under 2% (Jackman and Johnson 2005). Currently, it is evidenced that miR-126 is significantly implicated in the lymph node metastasis of SCLC. Since, a panel of genes that are targeted by miR-126, such as GRM8 and DACH1 that are involved in inhibition of tumour growth were down-regulated in small cell lung cancer (SCLC) patients with lymph node metastasis (Dorsam and Gutkind 2007, Wang et al. 2018). MiR-126 would diminish NSCLC cell proliferation through its action on epidermal growth factor-like domain 7 (EGFL7), which is contributed to cell migration and angiogenesis (Sun et al. 2010). Hence, miR-126 up-regulation would decrease the expression of the target gene PIK3R2 (Fish et al. 2008), and in turn would inhibit the PTEN/PIK3CA/AKT pathway and Spred1 pathways, thus, decreasing the NSCLC cell proliferation and metastasis processes (Song et al. 2016). Moreover, miR-126 involved in inhibition of tumour proliferation and tumour angiogenesis by targeting VEGF-A signalling, through targeting endothelium of blood vessels (Chen et al. 2014).
Specific induction of the unique GPR15 expression in heterogeneous blood lymphocytes by tobacco smoking
Published in Biomarkers, 2019
Mario Bauer, Jörg Hackermüller, Jana Schor, Stephan Schreiber, Beate Fink, Arkadiusz Pierzchalski, Gunda Herberth
In this report, we highlighted the strong impact of chronic smoking on the imprinting of T cells for GPR15 occurring highly frequently in vascular circulation. Whether smoking-induced enrichment of GPR15+ lymphocytes in blood or appropriate tissue has a health-preventing effect of smoking for patients suffering from ulcerative colitis (Bridger et al.2002) or, in the opposite, has a health-threatening effect of smoking for patients suffering from incident psoriasis (Naldi 2016) could not be resolved in this study. Indeed, severe large intestine inflammation was rescued by the transfer of GPR15-sufficient Treg indicating that GPR15 plays a role in mucosal immune tolerance, at least in mice (Kim et al.2013). Therefore, whether the GPR15L-GPR15 interaction may be an option for systemic therapeutic intervention needs to be proven in human. In mice, first evidence was given by systemic application of a GPR15L in the form of fifth region of epidermal growth factor-like domain of TM (TME5) that alleviated an acute graft-versus-host disease by its proposed anti-inflammatory impact (Pan et al.2017).