Boster Pathways->Adhesion/Ecm/Cytoskeleton

ADHERENS JUNCTION PATHWAY

Adherens junctions are the protein complex found at cell-cell junctions in epithelial and endothelial tissues.

What Are Adherens Junctions?

Adherens junctions are multiprotein complexes found in epithelial cells near the apical membrane. And they are primarily responsible for mediating adhesion between homologous cells in all types of tissues. Adherens junctions bind the actin cytoskeleton to the plasma membrane, creating an elastic attachment between epithelial cells or between the extracellular matrix and the epithelial cells.
They are constantly being constructed and disassembled, enabling cells inside tissues to react to forces, biochemical signals, and structural changes throughout their microenvironment.

Types of Cell Junctions

1. Adhering junctions (Zonula adherens)

2. Tight junctions (Occuluding occludens)
3 Gap Junctions
4. Desmosomes (Macula adherens)

Categories Of Adherens Junctions

Adhesion junctions are categorized as adhesion belts or focal adhesions.

Adhesion belt, commonly known as the intermediate junction, refers to the formation of a continuous band-like structure between adjacent cells. The interaction of actin and cadherin forms an adhesion belt that binds two cells. And it is primarily responsible for regulating cell structure.

The association between the cell and the extracellular matrix is mediated by focal adhesion, also known as mechanical attachment. It is formed by the interaction of actin and integrin. Cell spreading and migration are aided by focal adhesion. It also plays a role in cell signaling.

The connection between cell junctions and the cytoskeleton may be more dynamic than originally considered and may rely on multiple, weak associations between the cadherin-catenin complex and the actin cytoskeleton or rely on other membrane-associated proteins (i.e. nectin and afadin)

Functions of Adherens Junction

Adherens junctions maintain the structural integrity of the tissue. They initiate and maintain cell adhesion as well as control the actin cytoskeleton. Adherens junctions foster homologous cell adhesion and allow further tissue structure and differentiation during embryonic development.

Adherens junctions play a role in tissue homeostasis and regulation of epithelial and endothelial cell permeation. Adherens junctions also facilitate intercellular communication and signaling conduction, mediate touch inhibition of cell development, increase apoptosis resistance, and control cell form and polarity.

Mechanism of Adherens Junction

The Mechanism of Adhesion Belt

Cadherin is a single-channel transmembrane glycoprotein that belongs to the typical cadherin family of calcium-dependent adhesion proteins. The major component of the adhesion Belt, E-cadherin, is found in all epithelial tissues.It is the primary calmodulin (CaM) that keeps epithelial cells attached to one another. E-cadherin is made up of five cadherin repeats (EC1EC5), a transmembrane domain, and two cytoplasmic domains (the juxtamembrane domain that binds to p120-catenin and the cadherin domain that links to -catenin).The EC domain forms a trans-cadherin interaction between adjacent cells, initiates weak cell-cell adhesion, and forms adhesion molecule linkages. The Ca2+ binding in the EC domain ensures the correct conformation of the extracellular domain of cadherin. The cytoplasmic domain includes a highly phosphorylated region that mediates the binding of E-cadherin to β-catenin and participates in signal transduction.

When the highly-conserved cytosolic domain of E-cadherin binds to the intracellular ligand β-catenin, β-catenin is linked to actin to maintain cell polarity, intercellular connectivity, and signal transduction. β-catenin plays a dual role in cells. As a cytoskeletal protein, β-catenin anchors the E-cadherin on the surface of the cell membrane to the cytoskeleton through α-catenin, forming an adhesive junction E-cadherin/β-catenin complex. The E-cadherin/β-catenin complex is the core for the formation of the adhesion belt, which mediates homologous adhesion, maintaining the polarity and integrity of normal epithelium.

The adhesion is closely related to tumor invasion and metastasis. As a signal transduction protein, β-catenin takes part in the Wg/Wnt signaling pathway mediated by colon adenomatous polyp protein (APC)/β-catenin/T cytokine/lymphocyte proliferation factor 1 (Tcf1/Lef-1) complex. The pathway is associated with the transformation of epithelial-mesenchymal cells and excessive proliferation and invasion of tumor cells. Down-regulation or deletion of E-cadherin is significantly related to tumor dedifferentiation, intimate growth, metastasis, and poor prognosis.

Mechanism of Focal Adhesion

Integrins are a class of heterologous cell adhesion molecules that are ubiquitous on the surface of vertebrate cells. And they rely on Ca2+ or Mg2+. Integrins are the core proteins of focal adhesions, mediating the mutual recognition and adhesion between cells and extracellular matrices. So integrins serve as a messenger for the connection between external cells and the internal structure of cells.

Integrins are a transmembrane heterodimer. Two subunits of integrins, alpha and beta chains, are glycosylated and joined together by non-covalent bonds. Integrins bind to extracellular matrix proteins through their extracellular globular domains and link to actin through the intracellular tails, mediating the adhesion of cells to the extracellular matrix.

Integrins are also involved in signal transduction, including both "from the inside to the outside" and "from the outside to the inside" signals. The signal transduction function of integrins is dependent on focal adhesion kinase (FAK), which in turn depends on the formation of adhesion plaques. FAK phosphorylates some proteins, causing a cascade of signal amplification reactions. Signal transduction involving integrins and some other cell surface molecules affects many behaviors of cells, including motion, growth, and cell survival.

Diseases Related with Adherens Junction

Adherens junctions between vascular endothelial cells (EC) are an important basis for angiogenesis and maintenance. Adhesive connections are widely distributed between ECs and are essential for maintaining vascular integrity and stability. It is well known that the integrity of the vessel wall and sustained homeostasis are fundamental to ensure normal blood circulation. If pathological factors in the internal environment such as inflammation and oxygen free radicals, act on vascular endothelial cells, the adhesion between endothelial cells is reduced, which leads to the destruction of vascular integrity and stability, causing vascular endothelial damage and a series of pathological changes such as increased vascular permeability, vascular leakage, and atherosclerosis, leading to cardiovascular and cerebrovascular diseases.

In biological behavior, infiltration and metastasis are the most important characteristics of cancer and are the leading cause of death in patients. The loss of cancer cell adhesion is the first and a key step in cancer infiltration and metastasis. The process of tumor invasion and metastasis is an alternating process of adhesion and de-adhesion. The cell connection between the tumor cells and the surrounding environment is dynamically changing. So the strength of the superiority (the balance between adhesion and de-adhesion) determines the behavior of the tumor cells.

Many studies have confirmed that E-cadherin is negatively correlated with tumor invasion and metastasis, probably because E-cadherin can promote the homologous adhesion of tumor cells and keep them shedding from the tumor. In vitro experiments showed that the tumor cell line with E-cadherin expression had no innateness, while the tumor cell line with affinitive phenotype had no E-cadherin expression.

Interaction with other pathways

In addition to ensuring the cadherin-catenin complex's stability and connecting adherens junctions to the actin cytoskeleton, molecules involved in adheren junction pathway also affects other pathways as discused below.

Wnt/β-catenin signaling

β-catenin is an important molecule that connects adherens junctions to the Wnt/Wingless signaling pathway. The phosphorylation of -catenin by glycogen synthase kinase (GSK)-3 is suppressed in the presence of Wnt ligands, resulting in decreased ubiquitination-dependent degradation of -catenin.
Hippo-YAP pathway

The Hippo-YAP pathway is involved in organ size control, and its dysregulation is important in tumor growth and development. Yes-Associated Protein (YAP), (a transcription coactivator controlled by the Hippo tumor suppressor pathway) inhibits E-cadherin junction formation through altering actin cytoskeleton architecture.
Hedgehog signaling Pathway

The Hedgehog (Hh) signaling pathway regulates cell proliferation, migration, and differentiation during development, and its dysregulation has been linked to a number of human malignancies. Studies have shown that α-catenin inhibits Hedgehog signaling while loss of α-catenin leads to activation of hedgehog signaling
NF-κB signaling Pathway

The nuclear factor B (NF-B) signaling pathway is important in a variety of functions, including cell proliferation, survival, apoptosis, angiogenesis, migration, invasion, and immunological response. Depletion of α-catenin activates NF-κB signaling in the skin and where the NF-κB pathway plays a causal role in skin tumorigenesis. Also inhibition of NF-κB signaling mediates the tumor-suppressing effect of α-catenin.