Cell and Extracellular Matrix Interactions in a Dynamic Biomechanical Environment:
Michel R. Labrosse in Cardiovascular Mechanics, 2018
Ligand-binding affinity to integrins can be modulated by the activation state of the integrin. When in an inactive, low-affinity state, the ligand-binding pocket is closed and is further obscured by the bending of the integrin legs, orienting the head and ligand-binding regions toward the cell membrane (Hynes 2002, Nishida et al. 2006, Gahmberg et al. 2009). Inactive integrins are considered in a low-affinity state because small ligands such as RGD peptides are still able to bind (Beer et al. 1992). An intermediate-affinity state can be achieved by a conformational change, extending the integrin legs to orient the integrin head toward the extracellular space while still keeping the ligand-binding pocket closed (Gahmberg et al. 2009). Finally, a high-affinity state occurs when the integrin is extended and the ligand-binding pocket is open (Hynes 2002, Gahmberg et al. 2009). A number of factors can regulate integrin activation state, including cations. The β-1 domain contains an adjacent-to-MIDAS (ADMIDAS) site, which inactivates integrin when Ca2+ is bound and activates integrin when Mn2++ is bound (Humphries et al. 2003). Inside-out signaling via molecules’ binding to the integrin’s cytoplasmic tail can also regulate activation, with talin binding promoting an active conformation (Tadokoro et al. 2003) and filamin binding inhibiting activation (Kiema et al. 2006). Both talin and filamin are linker molecules that join integrins to the actin cytoskeleton.
Overview of Cell Adhesion Molecules and Their Antagonism
Bruce S. Bochner in Adhesion Molecules in Allergic Disease, 2020
Although their intracytoplasmic segments are relatively short, integrins interact with extracellular cytoskeletal components, such as actin and talin. The name integrins derives from the concept that these molecules “integrate” information from the extracellular milieu to intracellular compartments. Recently, it has been established that integrins are capable of bidirectional signaling, as they also transduce signals “inside out” (15). Thus, many integrins constitutively have minimal ability to bind their ligands. Upon activation of the cell, integrins undergo conformational changes that permit binding of divalent cations by the α-subunit and markedly increase their avidity for ligand. The presence of conformationally dissimilar forms has been confirmed by the description of monoclonal antibodies (mAb) specific for individual integrins at distinct states of activation.
Mechanotransduction Mechanisms of Hypertrophy and Performance with Resistance Exercise
Peter M. Tiidus, Rebecca E. K. MacPherson, Paul J. LeBlanc, Andrea R. Josse in The Routledge Handbook on Biochemistry of Exercise, 2020
The family of integrin proteins, 24 in all, are heterodimeric consisting of 18 α and 8 β subunits (13). As transmembrane proteins, the integrin physically connects the extracellular matrix to the intracellular space. Within the cell, the integrin indirectly connects to the actin cytoskeleton through scaffolding proteins positioned at the integrin's cytoplasmic tail such as talin, kindlin, and paxillin. Thus, through its transmembrane nature, the integrin allows communication in a bidirectional manner—both in an inside-out and outside-in fashion (96). Interestingly, research has shed light upon the extended physical continuity from the cytoskeleton into the nucleus, made possible by the linker of the nucleoskeleton and cytoskeleton (LINC) complex (109). This continuous physical link from the extracellular space, through the integrin to the cytoskeleton, and into the nucleus via the LINC complex, directly influences gene expression in a matter of seconds upon mechanical activity, such as muscle tension produced with exercise.
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.
Recent advances in molecular biomarkers for patients with hepatocellular carcinoma
Published in Expert Review of Molecular Diagnostics, 2019
Shinichi Umeda, Mitsuro Kanda, Yasuhiro Kodera
Talin 1 (TLN1) is an adaptor protein that conjugates integrins to the cytoskeleton and regulates integrin and focal adhesion signaling [58]. Chen et al. determined TLN1 levels in 200 HCC patients and downregulation of TLN1 were significantly correlated with younger age, larger tumor size, higher α-fetoprotein levels and poor prognosis [48]. They also found that TLN1 knockdown induced EMT by regulating E-cadherin, N-cadherin, vimentin, and β-catenin. Silencing TLN1 promoted the growth of lamellipodia and enhanced cell migration and invasion [48]. Western blot analysis of EMT-associated cancer pathway proteins revealed that phosphorylated ERK1/2 was significantly elevated in TLN1 knockdown cells [48]. They concluded that TLN1 acts as a tumor suppressor to inhibit EMT, migration, and invasion of HCC cells by decreasing activation of the ERK1/2 pathway and that TLN1 is a potential prognostic biomarker for HCC patients.
Heterogeneous Differentiation of Highly Proliferative Embryonal Carcinoma PCC4 Cells Induced by Curcumin: An In Vitro Study
Published in Nutrition and Cancer, 2021
Geetha Viswanathan, Lip Yong Chung, Usha K. Srinivas
Focal adhesions are sites of tight adhesion between cells in culture and the underlying extracellular matrix (22). Focal adhesions form structural links between the actin cytoskeleton and the extracellular matrix and are involved in signaling pathways that control cell growth, proliferation, and migration. We evaluated the localization of key components of focal adhesion complexes, including integrin β-1, talin, paxillin, and FAK. Figure 5A presents the reduction in the cell surface expression of the β-1 subunit of integrin observed in curcumin-induced differentiated cells. The distinct peripheral localization of talin and paxillin to focal adhesion complexes in treated cells increased when compared with the control cells (Figure 5B). The FAK protein was observed throughout the cytoplasm in untreated control PCC4 cells. In contrast, FAK clearly localized to focal adhesions in curcumin-treated cells at 72 h (Figure 5B). Together, the increase in levels and the peripheral localization of talin, paxillin, and FAK indicate that focal adhesion formation was enhanced in differentiated cells.