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Immunohistochemical Characterization of Extracellular Matrix in Tumor Tissues
Published in Róza Ádány, Tumor Matrix Biology, 2017
On the other hand, large proteoglycans revealed with antibody 2B1 were considered to locate in young (immature) loose connective tissues. This was observed in so-called specific stroma of tumor tissues, in which the interstitial mesenchymal cells may be stimulated to proliferate by tumor cells. Recently, versican118 and M-type proteoglycan119 have been found to have epidermal growth factor (EGF)-like domains. It is quite conceivable that tumor cells stimulate mesenchymal cells with an FGF-like factor produced by the tumor cells themselves, whereas the mesenchymal immature cells, which are stimulated to proliferate, produce large proteoglycan resembling versican having an EGF-like domain, which makes a favorable environment for tumor growth. Usually, the immature mesenchymal cells that were 2B1-positive were observed to locate in perivascular portions or perimuscular parts. The 2B1-positive cells were scanty in adult tissues, though they were numerous in young or fetal tissues. Recently, we confirmed that a larger number of 2B1-positive cells were seen in the dermis of 22-d-old rats, but they were scanty in that of old rats. Our previous experimental study showed that the subcutaneously innoculated Ehrlich tumor cells were most vigorously proliferating in dermis of 22-d-old mice than those in older ones.120 The results may be owed to the subcutaneous connective tissue containing numerous 2B1-positive cells, providing a favorable environment for the growth of innoculated tumor cells in younger mice.
The Gene for t-PA
Published in Cornelis Kluft, Tissue-Type Plasminogen Activator (t-PA): Physiological and Clinical Aspects, 1988
Tor Ny, Monica Ohlsson, Leif Strandberg
Examination of mammalian and viral genes coding for the EGF-like sequences has led to the suggestion that the arrangements of domains in these proteins emerge by means of exon shuffling.42–45 In these genes the EGF-like domain often coincides with an exon-intron junction. However, in the notch gene each EGF-like repeat is not coded for by separate exons, and the exon-intron junctions which interrupt some of the repeats are not always at the same position.54 The homology between the notch protein and the other proteins containing EGF-like domains suggests that these proteins share a common ancestor. However, it has to be determined if the arrangement of the proteins has evolved through exon shuffling alone or if other mechanisms have been involved.
Effects of Medin on Smooth Muscle Cells
Published in Gilles Grateau, Robert A. Kyle, Martha Skinner, Amyloid and Amyloidosis, 2004
A. Persson, S. Peng, P. Gerwins, X. Fu, P. Westermark
AMed or medin amyloid is the most common form of senile amyloid found with an occurrence of almost 100% in the population above fifty years of age (1). The name medin is derived from its localization to the media of arteries. A recent study by Peng and co-workers (2) shows that it is mainly found in arteries of the upper part of the body. Whether medin has any effect or is involved in any disease still needs to be studied. But given the fact that other amyloid proteins are causing toxicity and disease we believe that medin might have a similar effect in vessels and thus might be involved in several pathological conditions of arteries. Medin is a 50-amino acid long internal fragment of the precursor protein lactadherin (3). Lactadherin is a 46 kD large protein composed of 364 amino acids. It contains three different domains; an EGF-like domain in the N-terminus and coagulation factor V- and VIII-like domains in the C-terminus. The EGF-like domain of lactadherin contains the tripeptide RGD, which binds integrins, whereas the C-terminus binds phosphatidyl serine (4,5). Lactadherin was first discovered in breast milk but it is expressed by various cell types, such as smooth muscle cells of arteries (3). Many functions have been ascribed lactadherin. Given the similarity to coagulation factor V and VIII Shi and Gilbert (6) demonstrated that lactadherin, in vitro, functions as an anticoagulant by competing for the membrane binding sites of factor V and VIII. Recent studies show that lactadherin might act as a linker between macrophages and dying cells and thus be involved in apoptosis. Lactadherin binds to phosphatidyl serine on dying cells and to integrins on macrophages, thereby facilitating engulfment (7, 8). How and why medin is formed from lactadherin is not known. The purpose of this study was to examine the effects of medin amyloid in vitro.
Dynamic Changes of AREG in the Sclera during the Development of Form-Deprivation Myopia in Guinea Pigs
Published in Current Eye Research, 2022
Man She, Bing Li, Tao Li, Xiaodong Zhou
AREG is a ligand for epidermal growth factor receptor (EGFR) synthesized as a membrane-anchored precursor protein that behaves as an autocrine or paracrine factor.5 It expressed on the cell surface with an extracellular EGF-like domain and an intracellular domain.20 After AREG binding to the EGFR, the ectodomain activates the intracellular signal cascade reaction, and concomitantly induces migration of unshed proAREG from the plasma membrane to the nucleus, which mediates cell survival, proliferation, differentiation and movement and participates in various of physiological processes such as axonal and neuronal growth.9,21,22 Similar to the previous reports, in this study, AREG was found located in the cytoplasm and the nuclei, as well as the membrane element of these two parts. However, how AREG functions on the downstream molecules and whether the nuclei translocation rate of AREG was associated with FDM requires further studies.
NRG1 and NRG2 fusions in non-small cell lung cancer (NSCLC): seven years between lights and shadows
Published in Expert Opinion on Therapeutic Targets, 2021
Domenico Trombetta, Angelo Sparaneo, Federico Pio Fabrizio, Concetta Martina Di Micco, Antonio Rossi, Lucia Anna Muscarella
Because of their transmembrane disposition, the proNRGs are composed of three blocks: the N‐terminal extracellular domain, the transmembrane domain, and the C‐terminal intracellular region. The N‐terminal extracellular block includes the EGF‐like domain, consisting of six cysteine residues, which is critical for ErbB receptor binding and activation [21]. The NRGs bind with different affinity and activate the ErbB2-4 receptors promoting cell proliferation, motility and invasion associated with the neoplastic processes [21,22]. Specifically, the ErbB1, ErbB2, ErbB3, and ErbB4 constitute the ErbB family of transmembrane receptor tyrosine kinases (RTKs); they are composed of a large extracellular ligand-binding domain, a transmembrane domain, a small intracellular juxtamembrane domain, a kinase domain, and a C-terminal tail [23]. After binding ligands, these transmembrane receptors form hetero- or homodimers, which induce the phosphorylation of their intrinsic kinase domain, resulting in the activation of the downstream PI3K–AKT and MAPK pathways [24].
Is the endogenous ligand for PEAR1 a proteoglycan: clues from the sea
Published in Platelets, 2021
Caroline Kardeby, Foteini-Nafsika Damaskinaki, Yi Sun, Stephen P. Watson
PEAR1 is a part of the Multiple epidermal growth factor (EGF)-like domain family and is also known as multiple EGF-like domains protein 12 (MEGF12) and JEDI1. PEAR1 is a single transmembrane protein with 15 EGF-like repeats (Figure 1). Crosslinking of PEAR1 in platelets by PEAR1-specific antibodies or sulfated polysaccharides induces Src family kinase phosphorylation of the cytoplasmic tail leading to platelet activation [1,3–5]. One study has predicted six phosphorylation sites on the cytosolic tail of PEAR1, of which three have been experimentally proven; tyrosine 925, serine 953, and serine 1029 [1]. One of the predicted phosphorylation sites is tyrosine 943, which is present in a consensus site, YXXM, for binding to the SH2 domains of the 110 kDa regulatory subunit of the class I family of PI3K. Activation of the P85 catalytic unit by the regulatory subunit generates the lipid messenger phosphatidylinositol 3,4,5-trisphosphate (PIP3) which binds to pleckstrin homology (PH) domains in a variety of proteins, including the serine/threonine kinase Akt (Figure 1). Inhibitors of Src family kinases and PI3K abolish platelet activation induced by antibodies to PEAR1 or sulfated polysaccharides, demonstrating a unique mechanism of activation by a platelet surface glycoprotein [2–4] independent of Syk and PLCγ2, and major Ca2+ signaling [3]. PEAR1 has also been shown to activate PI3K in megakaryocytes [11] and in endothelial cells [8,9].