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13.11: Tight Junctions - Biology

13.11: Tight Junctions - Biology


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Sometimes, holding cells together, even with great strength, is not enough. In epithelia especially, a layer of cells may need to not only hold together but form a complete seal to separate whatever is in contact with the apical side from whatever is in contact with the basal side. That would be a job for The Tight Junction! Well, more accurately, for many tight junctions in an array near the apical surface. Perhaps the best example of the utility of tight junctions is in the digestive tract. The tight junctions that form between cells of the epithelial lining of the gut separate the food and its digestion products from the body at large, forcing macromolecule nutrients to be transported through the epithelial cell by endocytosis/transcytosis to the bloodstream where they can be most efficiently distributed. The tight junctions also form in blood vessels to prevent leakage of blood, and in a variety of organs where liquids must be contained.

An individual tight junction is formed by the interaction of claudins and occludins. They are each 4-pass transmembrane proteins with both N- and C-termini on the cytoplasmic side; the extracellular side has a very low pro le, consisting of one (claudin) or two (occludin) small loops. Because of their small size, when they interact, the membranes are brought together very closely. In order to actually form a seal between cells though, tight junctions must be lined up in close order all the way around the cell, and in fact, usually there are multiple lines, which one could think of as “backup” in case one line develops a leak. Claudin molecules have relatively small cytoplasmic domains and it is not clear whether there are significant interactions with other proteins. However, occludin has a large C-terminal cytoplasmic domain that contains a PDZ-binding domain. PDZ is a protein interaction motif of approximately 80-90 amino acids found in a number of signaling proteins, most often in use to hold signaling complexes near the membrane by interacting with a transmembrane protein, as would be the case here with occludin. These PDZ-containing proteins both have signaling functions and can act as adapters to the cytoskeleton, primarily the actin laments. Finally, although an exact mechanism is unclear, elevated levels of Ca2+, either extracellularly or perimembranously, is associated with tight junction assembly.


Tight Junctions

Abstract

Tight junctions are one mode of cell–cell adhesion in epithelial and endothelial cellular sheets. They act as a primary barrier to the diffusion of solutes through the intracellular space, create a boundary between the apical and the basolateral plasma membrane domains, and recruit various cytoskeletal as well as signaling molecules at their cytoplasmic surface. Evidences have been accumulated that claudins are essential membrane proteins of tight junctions, which form the paracellular permselective barrier. New insights into the molecular architecture of tight junctions allow us to now discuss the structure and functions of this unique cell–cell adhesion apparatus in molecular terms.


Tight Junctions: Location, Structure, and Function

Tight junctions are a type of cell junctions that play a role in cell adhesion and permeability of paracellular barrier. This BiologyWise post elaborates on where these junctions are found, their structure as well as their function.

Tight junctions are a type of cell junctions that play a role in cell adhesion and permeability of paracellular barrier. This BiologyWise post elaborates on where these junctions are found, their structure as well as their function.

Pathogens Target Tight Junction Proteins

Proteolytic enzymes from pollen, many viruses, dust mites, and enterotoxins from bacteria, like ,.Clostridium perfringens, interact with these junctions to bring about the loss of the epithelial barrier function.

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A cell junction is a multiprotein complex that links two neighboring cells or a cell to the extra cellular matrix. These complexes form the barriers guarding the inter cellular spaces, and thus, control the para cellular transport. They help in establishing communication between neighboring cells.

There are three basic types of cell junctions: anchoring junction, communicating or GAP junctions, and tight junctions. Anchoring junctions are protein complexes that are used to anchor the cells of a tissue either to each other or to the extra cellular matrix. Communicating junctions bring about direct chemical communication between adjacent cells. Tight junctions act as barriers that regulate the movement of ions, water, and other molecule via the para cellular space in the epithelial cells. We will now elaborate on the tight junctions in this article.

What are Tight Junctions?

These are also known as occluding junctions or zonulae occludentes. These junctions form the closest contacts as compared to the other cell junctions and can therefore form a barrier that is virtually impermeable to fluids. These are the most apical structures of the apical complex, and they form the demarcation between the apical and the basolateral membranes of the domains.

Where are Tight Junctions Found in the Body?

Tight junctions are required for cell adhesion in various tissues of the body. These structures are seen to be present on the epithelium cells that form the internal lining of the body. These are usually of one or two layers of cells. Recent studies have also highlighted their role in barrier function in the skin as well.

Numerous and highly complex tight junctions are usually found in the epithelial lining of the distal convoluted tubules, the collecting duct of nephrons, the blood brain barrier, and the part of the bile duct that transverses the liver. These linings are thus given the name “tight epithelia”.

Relatively fewer number and less complex tight junctions are present on the epithelial lining of the proximal tubules of the kidney. These linings are called “leaky epithelia”.

What is the Structure of Tight Junctions?

Tight junctions are usually made of trans-membrane proteins that are linked to a cytoplasmic plaque. Trans-membrane proteins are usually of two types: tetra-span and single-span trans-membrane proteins. Tetraspan proteins contain four membrane spanning domains, these include proteins like occludins, claudins, and tricellulins.

Occludins regulate the diffusion of hydrophilic molecules they are usually associated with the intramembrane strand of the actin filament. Claudins determine the ion selectivity of tight junctions and are required for junction assembly. Tricellulins are found in junctions with three cells and are required to bring about cell-cell adhesion.

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Single-span trans-membrane proteins include Junctional Adhesion Molecules (JAMs). JAM protein is required for adhesion between the endothelial cells and leukocytes as well as for maintaining cell polarization.

The cytoplasmic plaque is formed by a network of scaffolding and adaptor proteins, that are bound to cell signaling components as well as to the components of the cytoskeleton such as actin filaments. This complex acts as an interface between junctional membrane proteins and the cytoskeletal protein. ZO-1 is a scaffolding protein that interacts with membrane proteins like claudins and cell signaling protein. ZO-2 and ZO-3 are adapter proteins that bind to membrane proteins like occludin.

Tight junctions occur in a belt completely encircling the cells, for a solute, ion, or molecule to pass through the layer of cells, it has to be first taken inside the cell from one end and given out from the other side. The junction membrane proteins are arranged like beads on a thread of the cytoskeletal filaments and are cross-linked to each other.

What are the Functions of Tight Junctions?

They two main functions of Tight Junctions include para-cellular permeability and regulation of cell proliferation and polarization. As these multi-protein complexes are negatively charged, they selectively allow positively charged ions to pass through. These junctions are also known to be size selective―molecules with radii greater than 4.5 °A are usually excluded. These junctions may also determine the permeability of certain hydrophilic molecules via the para-cellular space. Physiological pH also seems to determine the permeability of these molecules.

Cell proliferation and regulation seems to play a major role in the development of differentiated tissues. Occludins present in tight junctions are required for suppression of cell proliferation, and the absence of these proteins may lead to uncontrolled cancerous growth of cells. Certain biochemical studies indicate that tight junctions are required for the maintenance of apico-basal polarity. Proteins that are required for cell polarization usually form the complexes at tight junctions.

Occludins are also seen to regulate migration of neutrophils across the epithelial cell layer. Claudins also function to regulate cell migration.

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The cell membrane structure and functions covered in this article should provide basic information associated with this cell organelle. Read on to know more.

The primary function of ribosomes is synthesis of proteins according to the sequence of amino acids as specified in the messenger RNA.

The plant cell refers to the structural component of the plant. This BiologyWise article provides you with the structure of plant cells along with the functions of its constituents.


Regulation of Airway Tight Junctions by Proinflammatory Cytokines

Epithelial tight junctions (TJs) provide an important route for passive electrolyte transport across airway epithelium and provide a barrier to the migration of toxic materials from the lumen to the interstitium. The possibility that TJ function may be perturbed by airway inflammation originated from studies reporting (1) increased levels of the proinflammatory cytokines interleukin-8 (IL-8), tumor necrosis factor α (TNF-α), interferon γ (IFN-γ), and IL-1β in airway epithelia and secretions from cystic fibrosis (CF) patients and (2) abnormal TJ strands of CF airways as revealed by freeze-fracture electron microscopy. We measured the effects of cytokine exposure of CF and non-CF well-differentiated primary human airway epithelial cells on TJ properties, including transepithelial resistance, paracellular permeability to hydrophilic solutes, and the TJ proteins occludin, claudin-1, claudin-4, junctional adhesion molecule, and ZO-1. We found that whereas IL-1β treatment led to alterations in TJ ion selectivity, combined treatment of TNF-α and IFN-γ induced profound effects on TJ barrier function, which could be blocked by inhibitors of protein kinase C. CF bronchi in vivo exhibited the same pattern of expression of TJ-associated proteins as cultures exposed in vitro to prolonged exposure to TNF-α and IFN-γ. These data indicate that the TJ of airway epithelia exposed to chronic inflammation may exhibit parallel changes in the barrier function to both solutes and ions.


TJs in disease

Defects in permeability

TJ transmembrane proteins are affected in several inherited diseases, which suggests that the selectivity of the junctional diffusion barrier is physiologically important. For example, mutations in claudin 16 (which was originally called paracellin-1) and claudin 19 cause hypomagnesaemia (renal magnesium wasting) owing to a deficiency in paracellular magnesium resorption in the kidney (Konrad et al., 2006 Simon et al., 1999). The two proteins interact and are thought to form a paracellular cation pore. Similarly, mutations in claudin 14 and tricellulin cause hereditary deafness, which is likely to be the result of alterations in paracellular permeability (Riazuddin et al., 2006 Wilcox et al., 2001).

The WNK (with-no-K[Lys]) kinases WNK4 and WNK1, mutations in which cause hypertension (pseudohypo-aldosteronism type II) because of their effects on renal salt reabsorption and K + excretion (Wilson et al., 2001), are also thought to act through claudins. Disease is caused by WNK4 alleles that have gain-of-function mutations and therefore hyperstimulate claudin phosphorylation, which results in increased paracellular Cl – permeability and, subsequently, hypertension (Kahle et al., 2004 Yamauchi et al., 2004 Richardson and Alessi, 2008).

The expression of several TJ components is affected in various carcinomas. For example, the expression levels of ZO-1 and ZO-2 are dysregulated in different types of cancers and, in the case of breast cancer, low expression of ZO-1 has been correlated with a poor prognosis (Chlenski et al., 2000 Chlenski et al., 1999 Hoover et al., 1998 Kleeff et al., 2001 Martin et al., 2004 Morita et al., 2004 Resnick et al., 2005 Takai et al., 2005). Similarly, several junctional scaffolding proteins are bound and inactivated by viral oncogenes (Glaunsinger et al., 2001 Latorre et al., 2005). By contrast, ZONAB and its activating protein Apg2 are both upregulated in hepatocellular carcinomas, which suggests that this proliferation-promoting pathway is stimulated (Arakawa et al., 2004 Gotoh et al., 2004 Hayashi et al., 2002).

To what extent these alterations are a cause or a consequence of carcinogenesis is generally not clear. Nevertheless, claudin 1 has been shown to promote transformation and metastatic behaviour in colon cancer (Dhawan et al., 2005). The underlying molecular mechanism by which claudin 1 regulates migration is not clear. However, it might involve the association of claudin 1 with integrin-based complexes, similar to the role of claudin 11 in cell migration (Tiwari-Woodruff et al., 2001).

TJ proteins as targets of pathogens

TJ proteins are targeted by several types of pathogens, and these interactions often lead to junctional dissociation and the loss of epithelial barrier function. For example, proteolytic enzymes from pollen and dust mites, as well as enterotoxin from Clostridium perfringens, attack junctional membrane proteins, which results in paracellular leakage (Runswick et al., 2007 Sonoda et al., 1999 Wan et al., 1999). In addition, several TJ transmembrane proteins function as receptors for viruses. For example, claudin 1 functions as a co-receptor for the hepatitis C virus and is required for virus entry (Evans et al., 2007). Similarly, several of the TJ-associated members of the CTX-protein family, such as the coxsackievirus and adenovirus receptor (CAR) and JAM-A (which binds to reovirus), also act as viral receptors (Barton et al., 2001 Cohen et al., 2001 Walters et al., 2002). In some cases (e.g. hepatitis C virus), binding of virus to the TJ protein favours its entry into cells, whereas in other cases the interaction helps to overcome the junctional diffusion barrier to enable the virus to access its actual receptor (e.g. rotavirus) or to promote the release of virus from the epithelium (e.g. adenovirus) (Evans et al., 2007 Nava et al., 2004 Walters et al., 2002). Another striking example is provided by the bacterium Helicobacter pylori, which causes gastric ulcers and cancer (Pritchard and Crabtree, 2006). H. pylori translocates a protein called CagA into host cells. CagA associates with the ZO-1–JAM-A complex, which is thought to contribute to corruption of the gastric epithelial barrier (Amieva et al., 2003). Because the binding of CagA causes the redistribution of ZO-1 complexes, it is possible that ZO-1-associated signalling mechanisms contribute to the development of H. pylori-induced pathologies.


Intercellular Junctions

Cells can also communicate with each other via direct contact, referred to as intercellular junctions. There are some differences in the ways that plant and animal cells do this. Plasmodesmata are junctions between plant cells, whereas animal cell contacts include tight junctions, gap junctions, and desmosomes.

Plasmodesmata

In general, long stretches of the plasma membranes of neighboring plant cells cannot touch one another because they are separated by the cell wall that surrounds each cell. How then, can a plant transfer water and other soil nutrients from its roots, through its stems, and to its leaves? Such transport uses the vascular tissues (xylem and phloem) primarily. There also exist structural modifications called plasmodesmata (singular = plasmodesma), numerous channels that pass between cell walls of adjacent plant cells, connect their cytoplasm, and enable materials to be transported from cell to cell, and thus throughout the plant (Figure 2).

Figure 2. A plasmodesma is a channel between the cell walls of two adjacent plant cells. Plasmodesmata allow materials to pass from the cytoplasm of one plant cell to the cytoplasm of an adjacent cell.

Tight Junctions

A tight junction is a watertight seal between two adjacent animal cells (Figure 3). The cells are held tightly against each other by proteins (predominantly two proteins called claudins and occludins).

Figure 3. Tight junctions form watertight connections between adjacent animal cells. Proteins create tight junction adherence.

This tight adherence prevents materials from leaking between the cells tight junctions are typically found in epithelial tissues that line internal organs and cavities, and comprise most of the skin. For example, the tight junctions of the epithelial cells lining your urinary bladder prevent urine from leaking out into the extracellular space.

Desmosomes

Also found only in animal cells are desmosomes, which act like spot welds between adjacent epithelial cells (Figure 4). Short proteins called cadherins in the plasma membrane connect to intermediate filaments to create desmosomes. The cadherins join two adjacent cells together and maintain the cells in a sheet-like formation in organs and tissues that stretch, like the skin, heart, and muscles.

Figure 4. A desmosome forms a very strong spot weld between cells. Linking cadherins and intermediate filaments create it.

Gap Junctions

Gap junctions in animal cells are like plasmodesmata in plant cells in that they are channels between adjacent cells that allow for the transport of ions, nutrients, and other substances that enable cells to communicate (Figure 5). Structurally, however, gap junctions and plasmodesmata differ.

Figure 5. A gap junction is a protein-lined pore that allows water and small molecules to pass between adjacent animal cells.

Gap junctions develop when a set of six proteins (called connexins) in the plasma membrane arrange themselves in an elongated donut-like configuration called a connexon. When the pores (“doughnut holes”) of connexons in adjacent animal cells align, a channel between the two cells forms. Gap junctions are particularly important in cardiac muscle: The electrical signal for the muscle to contract is passed efficiently through gap junctions, allowing the heart muscle cells to contract in tandem.

In Summary: Cell Junctions

Animal cells communicate via their extracellular matrices and are connected to each other via tight junctions, desmosomes, and gap junctions. Plant cells are connected and communicate with each other via plasmodesmata.

When protein receptors on the surface of the plasma membrane of an animal cell bind to a substance in the extracellular matrix, a chain of reactions begins that changes activities taking place within the cell. Plasmodesmata are channels between adjacent plant cells, while gap junctions are channels between adjacent animal cells. However, their structures are quite different. A tight junction is a watertight seal between two adjacent cells, while a desmosome acts like a spot weld.


The tight junction (also referred to as a zonula occludens) is a site where the membranes of two cells come very close together. In fact, the outer leaflets of the membranes of the contacting cells appear to be fused. Tight junctions, as their name implies, act as a barrier so that materials cannot pass between two interacting cells. The protein components of the tight junction are arranged like beads on a string that span the adjacent membranes of each tight junction.

Tight junctions often occur in a belt completely encircling the cell. In a sheet of such cells, material cannot pass from one side of the sheet to the other by squeezing between cells. Instead, it must go through a cell, and hence the cell can regulate its passage. Such an arrangement is found in the gut, to regulate absorption of digested nutrients.

Summary:
Therefore basically it prevents the cell tissues from touching with each other so that the mode of transmission of substances are controlled by other means.


From:

http://www.biologyreference.com/Ce-Co/Cell-Junctions.html

Such complex is the tight junction pathway!!

Epithelia in multicellular organisms constitute the frontier that separates the individual from the environment. Epithelia are sites of exchange as well as barriers, for the transit of ions and molecules from and into the organism. Epithelial cells achieve this by providing cellular borders that cover external and internal surfaces throughout the body. Complexes between adjacent cells include Gap Junctions, Desmosomes, Adherens Junctions (AJs) and Tight Junctions (TJs). Such junctions are quite essential for the modulation of paracellular permeability in various epithelia. Vertebrate epithelial cells exhibit Tight Junctions that lie apical to Adherens Junctions. Tight Junctions have an organizing role in epithelial polarization and establish an apico-lateral barrier to the diffusion of solutes through the intracellular space (gate function). They also restrict the movement of lipids and membrane proteins between the apical and the basolateral membrane (fence function). Tight Junctions are highly ordered membrane contact sites or ‘kissing points’, comprising a network of intra-membrane fibrils (Ref.1). They comprise at least four types of transmembrane proteins, including Occludins, Claudins, JAMs (Junctional Adhesion Molecules) and Crb (Crumb), and a number of cytoplasmic peripheral proteins. Whereas the transmembrane proteins mediate cell-cell adhesion, the cytosolic Tight Junction plaque contains various types of proteins (e.g. PDZ proteins, such as the ZO (Zona Occludens) family) that link Tight Junction transmembrane proteins to the underlying cytoskeleton. These adapters also recruit regulatory proteins, such as protein kinases, phosphatases, small GTPases and transcription factors, to the Tight Junctions. As a result, structural (Actin and Spectrin) and regulatory (Actin-binding proteins, GTPases and kinases) proteins are juxtaposed with transmembrane proteins. This protein scaffolding facilitates the assembly of highly ordered structures, such as junctional complexes or signaling patches that regulate epithelial cell polarity, proliferation and differentiation (Ref.2).

Tight Junctions are located at the uppermost portion of the lateral plasma membrane, where the integral membrane proteins like Claudins appear to be involved in the homophilic and/or heterophilic interactions implicated in firm adhesions. Claudins have four hydrophobic transmembrane domains and two extracellular loops (the first loop is larger than the second). The extracellular loops, whose sequences are distinct in different Claudins, contribute to the formation not only of Tight Junction strands but also of ion-selective channels. Among all Claudins, Claudin-1 is rather ubiquitous whereas Claudin-6 is developmentally restricted and not expressed in adult tissues. Claudin-5 is considered to be endothethial cell specific. In general Tight Junction strands are linear co-polymers of Occludin, various Claudins and JAMs that attract cytoplasmic proteins containing PDZ domains have high affinity for the C-terminal sequences of these proteins. Several membrane proteins that participate in Tight Junction-scaffolding bind to the C-terminal YV sequences of several Claudins through their PDZ domains (Ref.3 & 4). Those which directly interact with C-terminus of Claudins include ZO1, ZO2, ZO3, Afadin, MUPP1 (Multiple PDZ Domain Protein-1), PATJ (Pals1-Associated Tight Junction Protein), PILT (Protein Incorporated Later into Tight Junctions), Spectrin/Fodrin, transcription factor ZONAB, aPKC (Atypical Protein Kinase-C), Protein 4.1 and F-Actin. ZO1 is also directly regulated by GPCR (G-Protein Coupled Receptor)/GN-Alpha12 (Guanine Nucleotide-Binding Protein-Alpha-12) whereas GPCR/GN-Alpha/Ras-based signaling activates ZO1 associated Afadin to establish firm adhesions. PATJ interacts with PALS1 (Protein Associated with Lin7-1 (Mouse Homolog)), Crb1 and Crb3 to form a tripartite Tight Junction complex involved in epithelial cell polarity (Ref.2).

It is most likely that aPKC binds to PALS1-PATJ-Crb, and phosphorylates Crb. aPKC also associates with the PAR-3 (Partitioning Defective-3)-PAR-6 polarity complex that is recruited to Tight Junction. PAR-3 and PAR-6 interacts with Crb and PALS1 complex and results in Tight Junction assembly and apicobasal polarity. The interaction between PAR-6 and PALS1 is regulated by CDC42 (Cell Division Cycle-42). PAR-6 interaction with GTP-bound CDC42, a key modulator of the Actin cytoskeleton, results in the activation of aPKC at sites of cell-cell junctions. Interestingly, the small GTPase CDC42 regulates different steps of polarized membrane trafficking, such as basolateral to apical transcytosis, apical endocytosis and biosynthetic transport (Ref.5). It is possible that the binding of CDC42 to PAR-6 links the Tight Junction PAR-3/PAR-6/aPKC/Crb/PALS1/PATJ/TIAM1 (T-Cell Lymphoma Invasion and Metastasis-1)/MARK2 (MAP/Microtubule Affinity-Regulating Kinase-2) complexes to a signaling pathway regulating F-Actin/Myosin/Tubulin cytoskeleton, polarized membrane transport and Tight Junction assembly. Furthermore, aPKC, PAR-6 and mLGL (Mammalian Lethal Giant Larvae) form another multi-protein complex in which mLGL is phosphorylated by aPKC. mLGL phosphorylation is required for its localization along the lateral membrane and regulates the ability of mLGL to interact with Stx4 (Syntaxin-4) and thus to direct protein trafficking. However, aPKC function is inhibited by PP2A (Protein Phosphatase-2A) (Ref.6).

Unlike Claudin, Occludin is a transmembrane phosphoprotein expressed in the Tight Junctions of both epithelial and endothelial cells. Occludin is likely to be involved in establishing the seal at the sites of junctional strands. Occludins directly interacts with ZO1, ZO2, ZONAB, VAP33 (VAMP (Vesicle-Associated Membrane Protein)-Associated Protein-A-33kDa), PALS2, ZAK (Sterile Alpha Motif and Leucine Zipper Containing Kinase-AZK), Cttn (Cortactin), Spectrin/Fodrin, Protein 4.1, Ctnn-Beta (Catenin-Beta), Ctnn-Alpha, Alpha-Actn (Alpha-Actinin), Afadin, PILT, Cgn (Cingulin), 7H6 Antigen and Sympk (Symplekin). The cytoplasmic plaque proteins like Cgn and Sympk participates in nuclear as well as cytoplasmic polyadenylation and activates CSTF (Cleavage Stimulation Factor 3' pre-RNA Subunit) and HSF1 (Heat Shock Transcription Factor-1) to regulate mRNA stability and localization, and cell adhesion/Apoptosis, respectively (Ref.7). Cttn/Ctnn-Beta/Alpha-Actn activates Actin-related proteins ARP2/3 to coordinate the initiation of new filaments. ZO2 recruits aPKC, Rab13, PKA (Protein Kinase-A) and other RabGTPases to facilitate vesicular trafficking and to recruit Claudin1 and ZO1 to the Tight Junction. Both PKA and aPKC control particular vesicle-mediated transport steps. Rab13 interacts directly with PKA and inhibits PKA-dependent phosphorylation of VASP (Vasodilator-Stimulated Phosphoprotein) that is essential for Actin-remodelling. Further cAMP/PKA/RabGTPases activity stimulate apically directed transcytosis and secretion in epithelial cells, budding of constitutive transport vesicles from the trans-golgi network to the cell surface. Rab proteins are therefore required to control PKA activities required for vesicle transport at different membrane compartments. Analogously, phosphorylation of SNAREs (SNAP Receptors), which includes v-SNARE (Vesicle-associated SNARE) and t-SNARE (Target-membrane SNARE) proteins by PKA is implicated in the regulation of vesicle release (Ref.8 & 9).

Further cytokines like TNF-Alpha (Tumor Necrosis Factor-Alpha) and TGF-Beta (Transforming Growth Factor-Beta) regulate Occludin levels near junction points. TNF-Alpha/TNFR (Tumor Necrosis Factor Receptor) activates the Itg (Integrin)/ILK (Integrin-Linked Kinase)/GSK3 (Glycogen Synthase Kinase)/p130Cas (Crk-Associated Substrate-P130)/JNK (c-Jun Kinase) signaling and perturb the stability of the Tight Junction barrier (Ref.10). To optimize the loss scaffold proteins like MAGI2 (Membrane Associated Guanylate Kinase Inverted-2) and MAGI3 bind to Ctnn-Beta and Vcl (Vinculin) at Occludin junctions to prevent PTEN (Phosphatase and Tensin Homolog) degradation, which then significantly decreases the cell proliferation activity of the Akt (v-Akt Murine Thymoma Viral Oncogene Homolog) through conversion of PIP3 (Phosphatidylinositol-3,4,5-Trisphosphate) to PIP2 (Phosphatidylinositol-4,5-Bisphosphate) and prevents junction disassembly. Increase of PTEN activity also suppresses the Itg/ILK/GSK3/p130Cas/JNK signaling by decreasing Akt-induced GSK3 activation and this alters the level of Occludins near the Tight Junctions. Similarly, TGF-Beta/TGF-BetaR (Transforming Growth Factor-Beta Receptor) binds firmly to Occludins and regulates junction dynamics by promoting PAR-3 induced cell adhesion near Occludin and JAM junctions (Ref.11).

The components of the PAR-3/PAR-6/aPKC complex near JAMs regulate several signaling mechanisms that control epithelial polarization. PAR-3 interacts with the cytoplasmic domains of JAMs and hence mediates junctional recruitment of the complex. PAR-3 regulates Tight Junction assembly through PAR-6/aPKC-independent mechanism by regulating Rac1 activation via TIAM1 to formulate F-Actin/Myosin binding and cell adhesion. aPKC and CDC42 regulates vesicular trafficking, organization of the microtubule network and polarized membrane traffic (Ref.12). Apart from these other cell adhesion regulators like ZO1, ZONAB, Protein 4.1, Afadin, Spectrin/Fodrin, PILT, Cgn, CASK (Calcium/Calmodulin-Dependent Serine Protein Kinase (MAGUK Family)), MAGI1, Alpha-Actn, F-Actin and Myosin also form plaques near the cytoplasmic domains of JAMs to promote firm adhesions. Tight Junction formation (JAMs/Cgn complex) contributes to the down-regulation of RhoA activation and RhoA effector pathways like RhoA Signaling and Actin-Based Motility in high-density epithelial cells by inhibiting GEFH1 (Guanine Nucleotide Exchange Factor-H1) and this influences cell migration and cell cycle progression. By contrast, PAR-6 is also linked to the loss of the epithelial phenotype TGF-Beta-induced epithelial-mesenchymal transition requires PAR-6 phosphorylation by TGF-BetaR. Phosphorylation triggers an interaction with the ubiquitin ligase SMURF1 (E3 Ubiquitin Ligase SMURF1), which has been proposed to target junction-associated RhoA for degradation and, hence, to induce disintegration of the junctional complex. Likewise PP2A induce disintegration of the junctional complex through direct inhibition of JAMs (Ref.2 & 11).

Tight Junctions also regulate epithelial proliferation by different molecular mechanisms, which generally suppress proliferation as well as cell density (and hence Tight Junction assembly) increases. Several proteins that localize to Tight Junctions as well as the nucleus lead to regulate gene expression. One of them is ZO1 that regulates proliferation and interacts with the Y-box transcription factor ZONAB, a protein that is required for normal proliferation rates. ZONAB regulates G1/S phase progression by two different mechanisms. First, it interacts with the G1/S phase regulator CDK4 (Cyclin-Dependent Kinase-4) hence, cytoplasmic sequestration of ZONAB by ZO1 results in reduced nuclear CDK4. Secondly, ZONAB functions in the transcriptional regulation of cell cycle regulators. Thus, the cytoplasmic sequestration of ZONAB and CDK4 results in co-regulation of two different mechanisms that affect G1/S phase transition. Another such protein is ZO2, which interacts with ZO1, enters the nucleus in proliferating cells and then binds with the hnRNP (mRNA-binding Protein), SAFB (Scaffold Attachment Factor-B) to inhibit the transcription factors, AP-1 (Activator Protein-1) and CEBP (CCAAT Enhancer Binding Protein) leading to the deregulation of epithelial cell proliferation and differentiation (Ref.1 & 13). Tight Junctions basically have two important functions in the establishment of epithelial barriers first, they regulate formation of the barriers by modulating cell proliferation, differentiation and polarization, and second, they control barrier function by restricting paracellular diffusion. The above mechanisms shed insights on the regulation of paracellular permeability and may pave way for new therapeutic strategies in drug delivery across epithelial barriers (Ref.14 & 15).


Cell-cell junctions

are formed by groups of proteins that anchor cells together side by side, connecting the actin skeletons of each.

An investigator is studying the myometrial cells of the uterus during pregnancy. Just prior to and during labor, it is noticed that the myometrial cells upregulate cell junctions to facilitate synchronization of uterine contraction. These cell junctions are made of which of the following protein(s)? 

Cell-cell junctions exam links

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Contributors:

Cell-cell junctions are protein structures that physically connect cells to one another.

Cell-cell junctions facilitate for cellular communication, boost tissue structure, help with transport of materials between cells, or create an impermeable barrier for certain substances.

Cell-cell junctions are only found between immobile cells of organs and tissues-- so mobile cells like sperm and macrophages don’t have these structures.

Cell-cell junctions are most abundant in epithelial tissue, which is found in skin and the innermost layer of the gastrointestinal tract.

However, these structures are also found in other organs like the heart, kidneys, and liver.

The three types of cell-cell junctions are adherens junctions, tight junctions, and gap junctions.

Adherens junctions are formed by groups of proteins that anchor cells together side by side and prevent their separation - making them “adhere” to one another.

Adherens junctions have three major components.

The first component are long filamentous proteins called actin filaments that are part of the cytoskeleton and help give a cell its shape.

The second component is protein plaques, which are protein structures within the cytoplasm that are anchored to the plasma membrane that bind to the actin filaments.

Third, are transmembrane proteins called cadherins which attach to the protein plaques on one side and transverse the plasma membrane and connect to cadherins of an adjacent cell, linking the two together.

In this way, adherens junctions create a continuous network of interconnected cells via actin, which ultimately ties all these cells together to prevent their separation and provides extra strength.

This is particularly important in tissues that are exposed to constant shearing or abrasive forces like the skin or gastrointestinal tract.

It’s a bit like the reinforcing steel bar or rebar that sits within cement blocks to give a wall extra strength.

Now, tight junctions, also known as occluding junctions, are protein structures that seal two plasma membranes of adjacent cells together.

As a result, they prevent water, small proteins, and bacteria from passing in between two adjacent cells.


Tight junctions

Tight Junctions Definition
Tight junctions are areas where the membranes of two adjacent cells join together to form a barrier. The cell membranes are connected by strands of transmembrane proteins such as claudins and occludins.

tight junctions Junctions between the plasma membranes of adjacent cells in animals that form a barrier, preventing materials from passing between the cells.
tissues Groups of similar cells organized to carry out one or more speci?c functions. Groups of cells performing a function in a multicellular organism.

Tight Junctions
The tight junction (also referred to as a zonula occludens) is a site where the membranes of two cells come very close together. In fact, the outer leaflets of the membranes of the contacting cells appear to be fused.

seal the membranes of adjacent cells together very effectively, the membranes are not actually in close contact over broad areas. Rather, they are connected along sharply defined ridges.

are very important in embryo development. In the blastula, these cadherin mediated cell interactions are essential to development of epithelium which are most important to paracellular transport, maintenance of cell polarity and the creation of a permeability seal to regulate blastocoel formation.

Part b shows two cell membranes joined together by a matrix of

. Part c shows two cells fused together by a desmosome. Cadherins extend out from each cell and join the two cells together. Intermediate filaments connect to cadherins on the inside of the cell.

The blood-testis barrier, maintained by the

between the Sertoli cells of the seminiferous tubules, prevents communication between the forming spermatozoa in the testis and the blood vessels (and immune cells circulating within them) within the interstitial space.

Illustrated in Figure 2 is a fluorescence digital image of an adherent culture of Madin-Darby canine kidney cells (MDCK line) stained with fluorescent probes targeting the nucleus (blue), nuclear pore complex proteins (red), and the

formed between epithelial cells (green) to demonstrate the .

between cells. Keratin is such a protein and because the keratins are unique to certain cell types, they are sometimes used to identify the origin of cancer in people in whom cancer has metastasized.

Animals have 3 main types of intercellular links:

, membranes of adjacent cells are fused, forming continuous belts around cells.
This prevents leakage of extracellular fluid.

Many vertebrates have double cones--two cones that are joined along their long axes by

, gap junctions or both. Nearly all classes of vertebrates have some variety of this form of receptor in their retinas. This feature is not found in mammals.

The structures responsible for the adhesion of epithelial cells are called cell junctions. The main cell junctions are interdigitations, desmosomes, zonula adherens (adherens junctions),

(zonula occludens) and gap junctions. 
Epithelial Tissue Review  - Image Diversity: cell junctions .

upon which cells can move about and be reorganized, making complex structures possible. In contrast, other multicellular organisms like plants and fungi have cells held in place by cell walls, so develop by progressive growth. Also, unique to animal cells are the following intercellular junctions:


A Laboratory Guide to the Tight Junction

A Laboratory Guide to the Tight Junction offers broad coverage of the unique methods required to investigate its characteristics. The methods are described in detail, including its biochemical and biophysical principles, step-by-step process, data analysis, troubleshooting, and optimization. The coverage includes various cell, tissue, and animal models.

Chapter 1 provides the foundations of cell biology of tight junction. Chapter 2 covers the Biochemical approaches for paracellular channels and is followed by chapter 3 providing the Biophysical approaches. Chapter 4 describes and discusses Histological approaches for tissue fixation and preparation. Chapter 5 discusses Light microscopy, while chapter 6 presents Electron microscopic approaches. Chapter 7 covers Transgenic manipulation in cell cultures, including DNA and siRNA, Mutagenesis, and viral infection. Chapter 8 covers transgenic manipulation in mice, including: Knockout, Knockin, siRNA knockdown, GFP/LacZ reporter, and overexpression. The final chapter discusses the future developments of new approaches for tight junction research.

Researchers and advanced students in bioscience working on topics of cell junction, ion channel and membrane protein will benefit from the described methods. Clinicians and pathologists interested in tissue barrier diseases will also benefit from the biochemical and biophysical characterization of tight junctions in organ systems, and their connection to human diseases.

A Laboratory Guide to the Tight Junction offers broad coverage of the unique methods required to investigate its characteristics. The methods are described in detail, including its biochemical and biophysical principles, step-by-step process, data analysis, troubleshooting, and optimization. The coverage includes various cell, tissue, and animal models.

Chapter 1 provides the foundations of cell biology of tight junction. Chapter 2 covers the Biochemical approaches for paracellular channels and is followed by chapter 3 providing the Biophysical approaches. Chapter 4 describes and discusses Histological approaches for tissue fixation and preparation. Chapter 5 discusses Light microscopy, while chapter 6 presents Electron microscopic approaches. Chapter 7 covers Transgenic manipulation in cell cultures, including DNA and siRNA, Mutagenesis, and viral infection. Chapter 8 covers transgenic manipulation in mice, including: Knockout, Knockin, siRNA knockdown, GFP/LacZ reporter, and overexpression. The final chapter discusses the future developments of new approaches for tight junction research.

Researchers and advanced students in bioscience working on topics of cell junction, ion channel and membrane protein will benefit from the described methods. Clinicians and pathologists interested in tissue barrier diseases will also benefit from the biochemical and biophysical characterization of tight junctions in organ systems, and their connection to human diseases.


Watch the video: Tight Junctions MCAT Mnemonic Preview (November 2022).