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Integrins, Integrin Regulators, and the Extracellular Matrix
Published in Bruce S. Bochner, Adhesion Molecules in Allergic Disease, 2020
Stephen W. Hunt, Sirid-Aimée Kellermann, Yoji Shimizu
Outside-in signaling is initiated by the integrin β subunit cytoplasmic domain-dependent rearrangement of cytoskeletal components and actin into organized structures, known as focal adhesion complexes (FACs), that are found in the area of the cell membrane interacting with the ECM (Fig. 3). Integrins are the major adhesive elements associated with focal adhesions, although other cell surface membrane proteins may be involved. Focal adhesions also include several cytoskeletal components, including talin, vinculin, α-actinin, tensin, and paxillin. These cytoskeletal proteins are involved in forming the framework of the FAC (113,114). Focal adhesion complexes serve as the major site of actin filament attachment at the contact surface. Formation of FACs in adherent cells is likely associated with cell spreading. Interestingly, cells that remain motile, nonadherent, or transiently adherent, such as lymphocytes, lack FACs. It is presumed that these cells must have similar cytoskeletal structures, but they are likely to be smaller, less distinctive, and transient.
Structure, Biochemical Properties, and Biological Functions of Integrin Cytoplasmic Domains
Published in Yoshikazu Takada, Integrins: The Biological Problems, 2017
Martin E. Hemler, Jonathan B. Weitzman, Renata Pasqualini, Satoshi Kawaguchi, Paul D. Kassner, Feodor B. Berdichevsky
Focal adhesions are discrete subcellular regions where the plasma membrane is in tight association with the underlying substrate. These subcellular complexes, which are specialized for anchoring microfilament bundles known as stress fibers,97 contain several cytoskeletal proteins, including α-actinin, vinculin, and talin. In a substrate-dependent manner, integrins also localize to focal adhesions, thus providing a transmembrane linkage between the extracellular matrix and the cytoskeleton.56,57,60,97,151 Protein kinase C152 and the majority of tyrosine-phosphorylated proteins71,153 also appear to concentrate within focal adhesions, suggesting that these complexes are important sites of cellular signaling.
Introduction
Published in Malgorzata Lekka, Cellular Analysis by Atomic Force Microscopy, 2017
The cytoskeleton interaction with associated proteins has been demonstrated to influence cellular elastic properties for cells expressing vinculin (a focal adhesion protein interacting with actin fibers). The loss of vinculin reflects in a noticeable reduction of cell adhesion, spreading and the presence of stress fibers. The comparison performed by Goldman et al. in 1998 showed that the vinculin-deficient F9 mouse embryonic carcinoma cells had lower Young’s modulus than the wild-type cells. The authors attributed these changes to altered actin cytoskeletal organization, indicating an important role of vinculin as an integral part of the cytoskeletal network [16].
Suspended cell lines for inactivated virus vaccine production
Published in Expert Review of Vaccines, 2023
Jiayou Zhang, Zhenyu Qiu, Siya Wang, Zhenbin Liu, Ziling Qiao, Jiamin Wang, Kai Duan, Xuanxuan Nian, Zhongren Ma, Xiaoming Yang
Talin is the most characteristic binding protein linking integrins to actin and is a major component of focal adhesions (FAs). Talin has two subtypes, namely talin-1 and talin-2. Talin-1 gene knockout cell lines were established in fibroblasts, and it was found that they could not activate their integrins nor bind to the fibrin in ECM, thus leading to a significant decline in cell adhesion [96]. Other studies have confirmed the role of talin-1 in carcinogenesis and provided a new therapeutic target for the treatment of hepatocellular carcinoma (HCC). Furthermore, talin-1 may promote cell adhesion by regulating the epithelial-mesenchymal transition (EMT) process [97]. Studies have also shown that T cells and T cell exocrines lacking talin-2 show reduced binding with integrin ligands ICAM-1 and MAdCAM-1 [113], demonstrating that knockdown of the talin-2 gene can reduce cell adhesion. Kindlins, which contain three members (Kindlin-1, Kindlin-2, and Kindlin-3), are key cell-ECM adhesion proteins and key activators of integrins. Kindlin-2, also known as mig-2, can directly bind to the β1- and β3-integrin tail [98]. Studies have shown that knockdown of the Kindlin-2 gene can prevent the activation of integrins, thus significantly affecting the adhesion ability of cells [99]. Additionally, deficiencies in Kindlin-1 and Kindlin-3 can lead to diseases. For example, Kindlin-1 deficiency causes skin weakness and blistering (called Kindler syndrome), and Kindlin-3 deficiency causes hemorrhagic disease and immune deficiency.
Serum claudin-5, claudin-11, occludin, vinculin, paxillin, and beta-catenin levels in preschool children with autism spectrum disorder
Published in Nordic Journal of Psychiatry, 2023
Ayhan Bilgiç, Hurşit Ferahkaya, Hülya Karagöz, İbrahim Kılınç, Vesile Meltem Energin
Vinculin and paxillin may be other important molecules for BBB and intestinal barrier functions. Vinculin is a cytoplasmic protein that functions in cell-matrix and cell-cell adhesions and regulation of apoptosis. This molecule also plays a role in the regulation of tight junctions in the intestinal barrier. Like occludin, the research by Vojdani and colleagues found an elevation in antibody production against vinculin in patients with celiac disease and supported its role in intestinal permeability [24]. Paxillin is first defined as a cytoplasmic scaffold/adaptor protein that plays a crucial role in focal adhesion. However, further studies demonstrate that it could also have functions in cell migration, proliferation, and as a regulator of mRNA trafficking and subsequent translation [28]. Therefore, as well as their potential effects on barrier structures, these two molecules contribute to the development of ASD by affecting many developmental and physiological processes.
2-Arylquinolines as novel anticancer agents with dual EGFR/FAK kinase inhibitory activity: synthesis, biological evaluation, and molecular modelling insights
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Mostafa M. Elbadawi, Wagdy M. Eldehna, Amer Ali Abd El-Hafeez, Warda R. Somaa, Amgad Albohy, Sara T. Al-Rashood, Keli K. Agama, Eslam B. Elkaeed, Pradipta Ghosh, Yves Pommier, Manabu Abe
Focal adhesion kinase (FAK) is a cytoplasmic non-receptor tyrosine kinase involved in signal transductions from cell adhesions to regulate different biological cell functions including survival and cell migration13,14. Also, it is activated and overexpressed in diverse cancer types controlling cancer proliferation, survival and metastasis. Thus, FAK has been identified as a promising druggable target for targeted cancer therapy. Currently, several FAK inhibitors, such as 2,4-diaminopyridine derivative GSK2256098 and 2,4-diaminopyrimidine derivative Defactinib (Figure 1), are currently being evaluated in clinical trials for cancer treatment, in addition to the 2,4-diaminopyrimidine derivative TAE-226 (Figure 1) which displayed potent antitumor impact in different cancer types in vivo and in vitro and usually used as a reference drug7,15,16. Noteworthy, it was established that the most affected colorectal cancer expressed high levels of EGFR and FAK that particularly correlated with tumour angiogenesis, cancer aggressiveness and poor prognosis17,18.