Molecular Architecture and Function of Matrix Adhesions
TL;DR: These cell adhesions play crucial roles in cell migration, proliferation, and determination of cell fate, and are mediated by membrane receptors such as the integrins, as well as many other components that comprise the adhesome.
Abstract: Cell adhesions mediate important bidirectional interactions between cells and the extracellular matrix. They provide an interactive interface between the extracellular chemical and physical environment and the cellular scaffolding and signaling machinery. This dynamic, reciprocal regulation of intracellular processes and the matrix is mediated by membrane receptors such as the integrins, as well as many other components that comprise the adhesome. Adhesome constituents assemble themselves into different types of cell adhesion structures that vary in molecular complexity and change over time. These cell adhesions play crucial roles in cell migration, proliferation, and determination of cell fate.
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TL;DR: Understanding the mechanisms of ECM remodeling and its regulation is essential for developing new therapeutic interventions for diseases and novel strategies for tissue engineering and regenerative medicine.
Abstract: The extracellular matrix (ECM) serves diverse functions and is a major component of the cellular microenvironment. The ECM is a highly dynamic structure, constantly undergoing a remodeling process where ECM components are deposited, degraded, or otherwise modified. ECM dynamics are indispensible during restructuring of tissue architecture. ECM remodeling is an important mechanism whereby cell differentiation can be regulated, including processes such as the establishment and maintenance of stem cell niches, branching morphogenesis, angiogenesis, bone remodeling, and wound repair. In contrast, abnormal ECM dynamics lead to deregulated cell proliferation and invasion, failure of cell death, and loss of cell differentiation, resulting in congenital defects and pathological processes including tissue fibrosis and cancer. Understanding the mechanisms of ECM remodeling and its regulation, therefore, is essential for developing new therapeutic interventions for diseases and novel strategies for tissue engineering and regenerative medicine.
1,686 citations
TL;DR: Changing views on the specificity of protein-heparan sulfate binding and the activity of HSPGs as receptors and coreceptors are discussed.
Abstract: Heparan sulfate proteoglycans are found at the cell surface and in the extracellular matrix, where they interact with a plethora of ligands. Over the last decade, new insights have emerged regarding the mechanism and biological significance of these interactions. Here, we discuss changing views on the specificity of protein-heparan sulfate binding and the activity of HSPGs as receptors and coreceptors. Although few in number, heparan sulfate proteoglycans have profound effects at the cellular, tissue, and organismal level.
1,251 citations
TL;DR: The evolution of ECM proteins was key in the transition to multicellularity, the arrangement of cells into tissue layers, and the elaboration of novel structures during vertebrate evolution, and this key role is reflected in the diversity ofECM proteins and the modular domain structures.
Abstract: Completion of genome sequences for many organisms allows a reasonably complete definition of the complement of extracellular matrix (ECM) proteins. In mammals this “core matrisome” comprises 300 proteins. In addition there are large numbers of ECMmodifying enzymes, ECM-binding growth factors, and other ECM-associated proteins. These different categories of ECM and ECM-associated proteins cooperate to assemble and remodelextracellularmatricesandbindtocellsthroughECMreceptors.TogetherwithreceptorsforECM-boundgrowthfactors,theyprovidemultipleinputsintocellstocontrolsurvival, proliferation, differentiation, shape, polarity, and motilityof cells. The evolution of ECM proteins was key in the transition to multicellularity, the arrangement of cells into tissue layers, and the elaboration of novel structures during vertebrate evolution. This key role of ECM is reflectedinthediversityofECMproteinsandthemodulardomainstructuresofECMproteins both allow their multiple interactions and, during evolution, development of novel protein architectures.
909 citations
Journal Article•
TL;DR: As a new kind of substrate of IIF, beta( 2)GP I transfectant can be used to detect anti-beta(2)GP-I antibodies and keep the immunofluorescent property of HEp-2 cells in IFANA test and can be use as substrate for routine IFANA detection.
Abstract: OBJECTIVE To establish an indirect immunofluorescent test so as to improve the sensitivity and specificity of examination of antibodies to beta(2)-glycoprotein METHODS Full-length beta(2)GP cDNA was obtained from human hepatocellular cancer cell line HepG2 by RT-PCR and cloned into the mammalian expression vector pEGFP-C1 The recombinant plasmid pEGFP-beta(2)GP was transfected into HEp-2 cells RT-PCR, immunoblotting (IBT), confocal fluorescence microscopy, and indirect immunofluorescent test (IIF) were used to confirm the expression, localization, and antigenicity of fusion protein of green fluorescent protein (GFP) Serum specimens from 19 patients suspected as with secondary antiphospholipid syndrome (APS), 1 patient diagnosed as with primary APS, and 10 normal persons were detected with IIF-IgG-beta(2)GP1, ELISA-IgG-ACL, and ELISA-IgG-beta(2)GP I simultaneously RESULTS (1) The HEp-beta(2)GP I cells thus obtained retained their ability of expression of beta(2)GP-I-GFP for more than ten generations This beta(2)GP-I-GFP showed the antigenicity of beta(2)GP-I with a characteristic feature (2) Seven of the 20 serum specimens from APS patients showed characteristic immunofluorescent pattern No serum specimen from normal persons showed immunofluorescent staining The comparison of results of the three methods showed that the concordance between IIF-IgG-beta(2)GP I and ELISA-IgG-beta(2)GP I was the most perfect (Kappa = 0886) (3) HEp-beta(2)GP I retained the immunofluorescent property of HEp-2 cell CONCLUSION As a new kind of substrate of IIF, beta(2)GP I transfectant can be used to detect anti-beta(2)GP-I antibodies Transfeted HEp-2 cells keep the immunofluorescent property of HEp-2 cells in IFANA test and can be used as substrate for routine IFANA detection
777 citations
TL;DR: In this paper, integrin-based adhesion has been studied as a model for studying the central role of adhesion in migration and the authors outline modes of migration, both integrindependent and independent in vitro and in vivo.
Abstract: Integrin-based adhesion has served as a model for studying the central role of adhesion in migration. In this article, we outline modes of migration, both integrin-dependent and -independent in vitro and in vivo. We next discuss the roles of adhesion contacts as signaling centers and linkages between the ECM and actin that allows adhesions to serve as traction sites. This includes signaling complexes that regulate migration and the interplay among adhesion, signaling, and pliability of the substratum. Finally, we address mechanisms of adhesion assembly and disassembly and the role of adhesion in cellular polarity.
694 citations
References
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TL;DR: The mesenchymal state is associated with the capacity of cells to migrate to distant organs and maintain stemness, allowing their subsequent differentiation into multiple cell types during development and the initiation of metastasis.
8,642 citations
"Molecular Architecture and Function..." refers background in this paper
...to play important roles in embryonic cell migration, organ development, and tumor cell invasion (Kalluri and Weinberg 2009; Thiery et al. 2009; Onodera et al. 2010)....
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...…enhanced cell-ECM adhesion – can occur in epithelial-mesenchymal transitions (EMT) or weaker variants of this process, which appear to play important roles in embryonic cell migration, organ development, and tumor cell invasion (Kalluri and Weinberg 2009; Thiery et al. 2009; Onodera et al. 2010)....
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TL;DR: Processes similar to the EMTs associated with embryo implantation, embryogenesis, and organ development are appropriated and subverted by chronically inflamed tissues and neoplasias and the identification of the signaling pathways that lead to activation of EMT programs during these disease processes is providing new insights into the plasticity of cellular phenotypes.
Abstract: The origins of the mesenchymal cells participating in tissue repair and pathological processes, notably tissue fibrosis, tumor invasiveness, and metastasis, are poorly understood. However, emerging evidence suggests that epithelial-mesenchymal transitions (EMTs) represent one important source of these cells. As we discuss here, processes similar to the EMTs associated with embryo implantation, embryogenesis, and organ development are appropriated and subverted by chronically inflamed tissues and neoplasias. The identification of the signaling pathways that lead to activation of EMT programs during these disease processes is providing new insights into the plasticity of cellular phenotypes and possible therapeutic interventions.
8,587 citations
"Molecular Architecture and Function..." refers background in this paper
...…enhanced cell-ECM adhesion – can occur in epithelial-mesenchymal transitions (EMT) or weaker variants of this process, which appear to play important roles in embryonic cell migration, organ development, and tumor cell invasion (Kalluri and Weinberg 2009; Thiery et al. 2009; Onodera et al. 2010)....
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TL;DR: Current structural and cell biological data suggest models for how integrins transmit signals between their extracellular ligand binding adhesion sites and their cytoplasmic domains, which link to the cytoskeleton and to signal transduction pathways.
8,275 citations
TL;DR: This work introduced a method for optically imaging intracellular proteins at nanometer spatial resolution and used this method to image specific target proteins in thin sections of lysosomes and mitochondria and in fixed whole cells to image retroviral protein Gag at the plasma membrane.
Abstract: We introduce a method for optically imaging intracellular proteins at nanometer spatial resolution. Numerous sparse subsets of photoactivatable fluorescent protein molecules were activated, localized (to approximately 2 to 25 nanometers), and then bleached. The aggregate position information from all subsets was then assembled into a superresolution image. We used this method--termed photoactivated localization microscopy--to image specific target proteins in thin sections of lysosomes and mitochondria; in fixed whole cells, we imaged vinculin at focal adhesions, actin within a lamellipodium, and the distribution of the retroviral protein Gag at the plasma membrane.
7,924 citations
"Molecular Architecture and Function..." refers background in this paper
...Photoactivatable light microscopy (PALM) shows that in focal adhesions, vinculin displays a scattered pattern, similar to the distribution of the doughnut-shaped particles (Betzig et al. 2006)....
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TL;DR: An understanding of how tissue cells—including fibroblasts, myocytes, neurons, and other cell types—sense matrix stiffness is just emerging with quantitative studies of cells adhering to gels with which elasticity can be tuned to approximate that of tissues.
Abstract: Normal tissue cells are generally not viable when suspended in a fluid and are therefore said to be anchorage dependent. Such cells must adhere to a solid, but a solid can be as rigid as glass or softer than a baby's skin. The behavior of some cells on soft materials is characteristic of important phenotypes; for example, cell growth on soft agar gels is used to identify cancer cells. However, an understanding of how tissue cells-including fibroblasts, myocytes, neurons, and other cell types-sense matrix stiffness is just emerging with quantitative studies of cells adhering to gels (or to other cells) with which elasticity can be tuned to approximate that of tissues. Key roles in molecular pathways are played by adhesion complexes and the actinmyosin cytoskeleton, whose contractile forces are transmitted through transcellular structures. The feedback of local matrix stiffness on cell state likely has important implications for development, differentiation, disease, and regeneration.
5,889 citations
"Molecular Architecture and Function..." refers background in this paper
..., fibroblasts, myocytes, or neurons) grow optimally on adherent surfaces that match the cells’ intrinsic elasticity (Discher et al. 2005)....
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...In fact, rigidity sensing can be a cell-type specific property, and cells (e.g., fibroblasts, myocytes, or neurons) grow optimally on adherent surfaces that match the cells’ intrinsic elasticity (Discher et al. 2005)....
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...Moreover, major differences are found between adhesion sites formed on compliant surfaces (sub-kPa to a few kPa), compared with those formed on rigid surfaces (hundreds of kPa to a few mPa) (Discher et al. 2005; Discher et al. 2009)....
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