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Current Opinion in Cell Biology Apr 2017Focal adhesion kinase (FAK) is a cytoplasmic protein-tyrosine kinase first identified at extracellular matrix and integrin receptor cell adhesion sites and is a key... (Review)
Review
Focal adhesion kinase (FAK) is a cytoplasmic protein-tyrosine kinase first identified at extracellular matrix and integrin receptor cell adhesion sites and is a key regulator of cell movement. FAK is activated by a variety of stimuli. Herein, we discuss advances in conformational-associated FAK activation and dimerization mechanisms. Additionally, new roles have emerged for FAK signaling at cell adhesions, adherens junctions, endosomes, and the nucleus. In light of these new findings, we review how FAK activation at these sites is connected to the regulation of integrin recycling-activation, vascular permeability, cell survival, and transcriptional regulation, respectively. Studies uncovering FAK signaling connections in unexpected places within cells have yielded important new regulatory insights in cell biology.
Topics: Adherens Junctions; Animals; Binding Sites; Cell Adhesion; Cell Movement; Endosomes; Enzyme Activation; Extracellular Matrix; Focal Adhesion Protein-Tyrosine Kinases; Humans; Integrins; Phosphorylation; Signal Transduction
PubMed: 28213315
DOI: 10.1016/j.ceb.2017.01.003 -
Biochimica Et Biophysica Acta.... Sep 2020Epithelial and endothelial monolayers are multicellular sheets that form barriers between the 'outside' and 'inside' of tissues. Cell-cell junctions, made by adherens... (Review)
Review
Epithelial and endothelial monolayers are multicellular sheets that form barriers between the 'outside' and 'inside' of tissues. Cell-cell junctions, made by adherens junctions, tight junctions and desmosomes, hold together these monolayers. They form intercellular contacts by binding their receptor counterparts on neighboring cells and anchoring these structures intracellularly to the cytoskeleton. During tissue development, maintenance and pathogenesis, monolayers encounter a range of mechanical forces from the cells themselves and from external systemic forces, such as blood pressure or tissue stiffness. The molecular landscape of cell-cell junctions is diverse, containing transmembrane proteins that form intercellular bonds and a variety of cytoplasmic proteins that remodel the junctional connection to the cytoskeleton. Many junction-associated proteins participate in mechanotransduction cascades to confer mechanical cues into cellular responses that allow monolayers to maintain their structural integrity. We will discuss force-dependent junctional molecular events and their role in cell-cell contact organization and remodeling.
Topics: Adherens Junctions; Blood Pressure; Cytoskeleton; Desmosomes; Endothelial Cells; Epithelial Cells; Humans; Intercellular Junctions; Mechanical Phenomena; Membrane Proteins; Tight Junctions
PubMed: 32360073
DOI: 10.1016/j.bbamem.2020.183316 -
Cold Spring Harbor Perspectives in... May 2017The cadherin-catenin adhesion complex is the key component of the intercellular junction (AJ) that contributes both to tissue stability and dynamic cell movements in... (Review)
Review
The cadherin-catenin adhesion complex is the key component of the intercellular junction (AJ) that contributes both to tissue stability and dynamic cell movements in epithelial and nonepithelial tissues. The cadherin adhesion complex bridges neighboring cells and the actin-myosin cytoskeleton, and thereby contributes to mechanical coupling between cells which drives many morphogenetic events and tissue repair. Mechanotransduction at cadherin adhesions enables cells to sense, signal, and respond to physical changes in their environment. Central to this process is the dynamic link of the complex to actin filaments (F-actin), themselves structurally dynamic and subject to tension generated by myosin II motors. We discuss in this review recent breakthroughs in understanding molecular and cellular aspects of the organization of the core cadherin-catenin complex in junctions, its association to F-actin, its mechanosensitive regulation, and dynamics.
Topics: Actins; Adherens Junctions; Animals; Cadherins; Catenins; Cell Adhesion; Cytoskeleton; Humans; Mechanotransduction, Cellular; Microtubules
PubMed: 28096263
DOI: 10.1101/cshperspect.a028738 -
Tissue Barriers Jan 2018Cell junctions are critical for cell adhesion and communication in epithelial tissues. It is evident that the cellular distribution, size, and architecture of cell... (Review)
Review
Cell junctions are critical for cell adhesion and communication in epithelial tissues. It is evident that the cellular distribution, size, and architecture of cell junctions play a vital role in regulating function. These details of junction architecture have been challenging to elucidate in part due to the complexity and size of cell junctions. A major challenge in understanding these features is attaining high resolution spatial information with molecular specificity. Fluorescence microscopy allows localization of specific proteins to junctions, but with a resolution on the same scale as junction size, rendering internal protein organization unobtainable. Super-resolution microscopy provides a bridge between fluorescence microscopy and nanoscale approaches, utilizing fluorescent tags to reveal protein organization below the resolution limit. Here we provide a brief introduction to super-resolution microscopy and discuss novel findings into the organization, structure and function of epithelial cell junctions.
Topics: Adherens Junctions; Epithelial Cells; Humans; Microscopy, Fluorescence; Tight Junctions
PubMed: 29420122
DOI: 10.1080/21688370.2017.1404189 -
Biomolecules Sep 2022Cell-cell junctions comprise various structures, including adherens junctions, tight junctions, desmosomes, and gap junctions. They link cells to each other in tissues... (Review)
Review
Cell-cell junctions comprise various structures, including adherens junctions, tight junctions, desmosomes, and gap junctions. They link cells to each other in tissues and regulate tissue homeostasis in critical cellular processes. Recent advances in cell-cell junction research have led to critical discoveries. Cell-cell adhesion components are important for the invasion and metastasis of tumour cells, which are not only related to cell-cell adhesion changes, but they are also involved in critical molecular signal pathways. They are of great significance, especially given that relevant molecular mechanisms are being discovered, there are an increasing number of emerging biomarkers, targeted therapies are becoming a future therapeutic concern, and there is an increased number of therapeutic agents undergoing clinical trials. Oesophageal squamous cell carcinoma (ESCC), the most common histological subtype of oesophageal cancer, is one of the most common cancers to affect epithelial tissue. ESCC progression is accompanied by the abnormal expression or localisation of components at cell-cell junctions. This review will discuss the recent scientific developments related to the molecules at cell-cell junctions and their role in ESCC to offer valuable insights for readers, provide a global view of the relationships between position, construction, and function, and give a reference for future mechanistic studies, diagnoses, and therapeutic developments.
Topics: Humans; Esophageal Squamous Cell Carcinoma; Adherens Junctions; Intercellular Junctions; Esophageal Neoplasms; Biomarkers
PubMed: 36291586
DOI: 10.3390/biom12101378 -
Cell Communication and Signaling : CCS Nov 2016The establishment, remodeling and maintenance of tissular architecture during animal development, and even across juvenile to adult life, are deeply regulated by a... (Review)
Review
The establishment, remodeling and maintenance of tissular architecture during animal development, and even across juvenile to adult life, are deeply regulated by a delicate interplay of extracellular signals, cell membrane receptors and intracellular signal messengers. It is well known that cell adhesion molecules (cell-cell and cell-extracellular matrix) play a critical role in these processes. Particularly, adherens junctions (AJs) mediated by E-cadherin and catenins determine cell-cell contact survival and epithelia function. Consequently, this review seeks to encompass the complex and prolific knowledge about E-cadherin roles during physiological and pathological states, particularly focusing on the influence exerted by the thyroid hormone (TH).
Topics: Adherens Junctions; Animals; Cadherins; Catenins; Epithelial Cells; Evolution, Molecular; Signal Transduction; Thyroid Hormones
PubMed: 27814736
DOI: 10.1186/s12964-016-0150-1 -
Cell Reports Jul 2022Cadherins and integrins are intrinsically linked through the actin cytoskeleton and are largely responsible for the mechanical integrity and organization of tissues. We...
Cadherins and integrins are intrinsically linked through the actin cytoskeleton and are largely responsible for the mechanical integrity and organization of tissues. We show that cadherin clustering stimulates and spatially guides integrin activation. Adherens junction (AJ)-associated integrin activation depends on locally generated tension and does not require extracellular matrix ligands. It leads to the creation of primed integrin clusters, which spatially determine where focal adhesions will form if ligands are present and where ligands will be deposited. AJs that display integrin activation are targeted by microtubules facilitating their disassembly via caveolin-based endocytosis, showing that integrin activation impacts the stability of the core cadherin complex. Thus, the interplay between cadherins and integrins is more intimate than what was once believed and is rooted in the capacity of active integrins to be stabilized via AJ-generated tension. Altogether, our data establish a mechanism of cross-regulation between cadherins and integrins.
Topics: Adherens Junctions; Cadherins; Cell Adhesion; Extracellular Matrix; Focal Adhesions; Integrins; Ligands
PubMed: 35858563
DOI: 10.1016/j.celrep.2022.111091 -
Mediators of Inflammation 2016Cellular junctions play a critical role in structural connection and signal communication between cells in various tissues. Although there are structural and functional... (Review)
Review
Cellular junctions play a critical role in structural connection and signal communication between cells in various tissues. Although there are structural and functional varieties, cellular junctions include tight junctions, adherens junctions, focal adhesion junctions, and tissue specific junctions such as PECAM-1 junctions in endothelial cells (EC), desmosomes in epithelial cells, and hemidesmosomes in EC. Cellular junction dysfunction and deterioration are indicative of clinical diseases. MicroRNAs (miRNA) are ~20 nucleotide, noncoding RNAs that play an important role in posttranscriptional regulation for almost all genes. Unsurprisingly, miRNAs regulate junction protein gene expression and control junction structure integrity. In contrast, abnormal miRNA regulation of junction protein gene expression results in abnormal junction structure, causing related diseases. The major components of tight junctions include zonula occluden-1 (ZO-1), claudin-1, claudin-5, and occludin. The miRNA regulation of ZO-1 has been intensively investigated. ZO-1 and other tight junction proteins such as claudin-5 and occludin were positively regulated by miR-126, miR-107, and miR21 in different models. In contrast, ZO-1, claudin-5, and occludin were negatively regulated by miR-181a, miR-98, and miR150. Abnormal tight junction miRNA regulation accompanies cerebral middle artery ischemia, brain trauma, glioma metastasis, and so forth. The major components of adherens junctions include VE-cadherin, -catenin, plakoglobin, P120, and vinculin. VE-cadherin and -catenin were regulated by miR-9, miR-99b, miR-181a, and so forth. These regulations directly affect VE-cadherin--catenin complex stability and further affect embryo and tumor angiogenesis, vascular development, and so forth. miR-155 and miR-126 have been shown to regulate PECAM-1 and affect neutrophil rolling and EC junction integrity. In focal adhesion junctions, the major components are integrin 4, paxillin, and focal adhesion kinase (FAK). Integrin 4 has been regulated by miR-184, miR-205, and miR-9. Paxillin has been regulated by miR-137, miR-145, and miR-218 in different models. FAK has been regulated by miR-7, miR-138, and miR-135. Deregulation of miRNAs is caused by viral infections, tumorigenesis, and so forth. By regulation of posttranscription, miRNAs manipulate junction protein expression in all cellular processes and further determine cellular fate and development. Elucidation of these regulatory mechanisms will become a new alternative therapy for many diseases, such as cancers and inflammatory diseases.
Topics: Adherens Junctions; Animals; Cadherins; Claudin-5; Humans; MicroRNAs; Occludin; Platelet Endothelial Cell Adhesion Molecule-1; Tight Junctions; Zonula Occludens-1 Protein; beta Catenin
PubMed: 27999452
DOI: 10.1155/2016/5078627 -
Experimental Cell Research Sep 2017Epithelial tissues are defined by polarized epithelial cells that are integrated into tissues and exhibit barrier function in order to regulate what is allowed to pass... (Review)
Review
Epithelial tissues are defined by polarized epithelial cells that are integrated into tissues and exhibit barrier function in order to regulate what is allowed to pass between cells. Cell-cell junctions must be stable enough to promote barrier function and tissue integrity, yet plastic enough to remodel when necessary. This remarkable ability to dynamically sense and respond to changes in cell shape and tissue tension allows cell-cell junctions to remain functional during events that disrupt epithelial homeostasis including morphogenesis, wound healing, and cell division. In order to achieve this plasticity, both tight junctions and adherens junctions are coupled to the underlying actomyosin cytoskeleton. Here, we discuss the importance of the junctional linkage to actomyosin and how a localized zone of active RhoA along with other Rho GTPases work together to orchestrate junctional actomyosin dynamics. We focus on how scaffold proteins help coordinate Rho GTPases, their upstream regulators, and their downstream effectors for efficient, localized Rho GTPase signaling output. Additionally, we highlight important roles junctional actin-binding proteins play in addition to their traditional roles in organizing actin. Together, Rho GTPases, their regulators, and effectors form compartmentalized signaling modules that regulate actomyosin structure and contractility to achieve proper cell-cell adhesion and tissue barriers.
Topics: Actin Cytoskeleton; Actomyosin; Adherens Junctions; Animals; Epithelial Cells; Humans; Intercellular Junctions; rho GTP-Binding Proteins
PubMed: 28363828
DOI: 10.1016/j.yexcr.2017.03.053 -
Traffic (Copenhagen, Denmark) Dec 2016Cadherins are the primary adhesion molecules in adherens junctions and desmosomes and play essential roles in embryonic development. Although significant progress has... (Review)
Review
Cadherins are the primary adhesion molecules in adherens junctions and desmosomes and play essential roles in embryonic development. Although significant progress has been made in understanding cadherin structure and function, we lack a clear vision of how cells confer plasticity upon adhesive junctions to allow for cellular rearrangements during development, wound healing and metastasis. Endocytic membrane trafficking has emerged as a fundamental mechanism by which cells confer a dynamic state to adhesive junctions. Recent studies indicate that the juxtamembrane domain of classical cadherins contains multiple endocytic motifs, or "switches," that can be used by cellular membrane trafficking machinery to regulate adhesion. The cadherin-binding protein p120-catenin (p120) appears to be the master regulator of access to these switches, thereby controlling cadherin endocytosis and turnover. This review focuses on p120 and other cadherin-binding proteins, ubiquitin ligases, and growth factors as key modulators of cadherin membrane trafficking.
Topics: Adherens Junctions; Animals; Cadherins; Cell Adhesion; Cell Membrane; Embryonic Development; Endocytosis; Humans; Protein Transport
PubMed: 27624909
DOI: 10.1111/tra.12448