CELL-CELL ADHESION AND CELL JUNCTION

SUBMITTED BY ASHISH PALODKAR MSC. BIOTECHNOLOGY 1 SEM

SUBMITTED TO DR ROHINI KESHAVA GUIDE

CONTENT

CELL-CELL INTERACTION CELL ADHESION CADHERINS SELECTIN INTEGRINS IMMUNOGOBULIN FAMILY CELL JUNCTION OCCULUDING JUNCTION TIGHT JUNCTION SEPTATE JUNCTION ANCHORING JUNCTION ADHEREN JUNCTION FOCAL JUNCTION DESMOSOMES HEMI-DESMOSOMES COMMUNICATING JUNCTION GAP JUNCTION PLASMDESMATA CHEMICAL SYNPASES SUMMARY BIBLOGRAPHY

This selectivity was first demonstrated in classical studies of embryo development. liver) specifically adhere to cell of the some tissue rather than to cells of a different tissue (e.membrane protein called ¶cell adhesion molecules· (CAM) . brain).g. which showed that cells from one tissue (e . Such selective cell-cell adhesion is mediated by trans.CELL ADHESION Cell-cell adhesion is a selective process such that cells adhere only to other cell of specific types.g.

CELL ADHESION TYPES OF CELL ADHESION 1. CELL-EXTRACELLULAR MATRIX . CELL-CELL ADHESION 2.

Are typically trans-membrane receptor and are composed of three domains : an intracellular domains that interacts with cytoskeleton. a trans membrane domain and an extracellular domain that interacts with other CAMs of same kinds (hemophilic binding ) or with other CAMs or the extracellular matrix (heterophilic binding) .CELL ADHESION MOLECULES Cell adhesion molecules are protein located on the cell surface involved with the binding with other cells or with the extracellular matrix (ECM) in the process called cell adhesion.

CADHERINS 4. SELECTIN 2.CELL ADHESION MOLECULES ARE DIVIDED INTO FOUR MAJOR GROUPS 1. INTEGRINS 3.IMMUNOGLOBULIN SUPERFAMILY (Ig) .

CELL ADHESION INTERACTION HOMOPHILIC BINDING : Interaction in which an adhesion molecule on the surface of one cell binds to the same molecule on the surface of another cell. selectin and an integrin) LINKER DEPENDENT BINDING: Interaction of adjacent cell adesion molecule on the surface of two cell binds with a help of linker molecule. HETROPHILIC BINDING : Interaction in which an adhesion molecule on the surface of one cell recognizes a different molecule on the surface of another cell (eg. .

CADHERIN Expressed in both invertebre and vertebrate Are main molecules holding cells together in early embryonic tissue Homophilic binding Calcium dependent formation of adheren junction and desmosomes Most cadherin are single pass trans-membrane glycoproteins about 700-750 amino acid long. which are structurally related to immunoglobulin (Ig) domains . They associate in the plasma membrane to form dimmers or larger oligomers as extracellular part of the polypeptide chain which is usually folded into five or six cadherin repeats.

rod like structure: the more Ca2+ ions that are bound. If Ca2+ is removed.The Ca2+ ions are positioned between each pair of cadherin repeats. the extracellular part of the protein becomes floppy and is rapidly degraded by proteolytic enzymes . locking the repeats together to form a stiff. the more rigid the structure is.

ALSO BINDS TO THE CADHERIN CYTOPLASMIC TAIL AND REGULATES CADHERIN FUNCTION. FUNCTION IN INTRACELLULAR SIGNALLING. .THE LINKAGE OF CLASSICAL CADHERINS TO ACTIN FILAMENTS THE CADHERINS ARE COUPLED INDIRECTLY TO ACTIN FILAMENTS BY THE ANCHOR PROTEINS -CATENIN AND -CATENIN. A THIRD INTRACELLULAR PROTEIN. -CATENIN HAS A SECOND. AND VERY IMPORTANT. CALLED P120.

P-cadherin and Ncadherin and are widely expressed during early differentiation E-cadherin is present in epithelial cells. Non-classical cadherins include proteins with known adhesive function such as desmosomal cadherins and protocadherin found in brain . N-cadherin in nerve cells and P-cadherin in placenta and epidermis.Divided as classical and non-classical cadherin Classical cadherin are E-cadherin.

which strengthen the binding of the blood cells to the endothelium.SELECTIN Single trans-membrane protein with highly consereved lectin domain Heterophilic binding Calcium dependent cell-cell adhesion in the bloodstream. . P-selectin in blood platelets and E-selectin in endothelial cells They are attached to actin filament with an anchor protein they collaborate with integrins. Three types of selectin: L-selectin in blood cells(leukocytes).

The selectin attaches to the actin cytoskeleton through anchor proteins that are still poorly characterized. (B) How selectins and integrins mediate the cell-cell adhesions required .(A) The structure of P-selectin.

Are active during inflammatory response have an important role in binding white blood cells to endothelial cells lining blood vessels. thereby enabling the blood cells to migrate out of the bloodstream into a tissue .

INTREGRIN Heterophilic binding Present in verterbrates At least 24 integrin heterodimer composed of 18 types of subunits and 8 types of subunits in various combination. Integrin subunits span the plasma membrane and in general have very short cytoplasmic domains of about 40²70 amino acids where as beta-4 subunits have 1088 amino acid The molecular mass of the integrin subunits can vary from 90 kDa to 160 kDa Helps in focal adhesion and hemi-desmosomes .

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Protein named Talin activates the newly formed integrin which is bent in position, attaches to the tail Calcium and magnesium dependent It is hepls in formation of focal adhesion by forming a complex of ligand, integrin molecule and associste plaques protein Not only do integrins perform this outside-in signalling, but they also operate an inside-out mode. Thus, they transduce information from the ECM to the cell as well as reveal the status of the cell to the outside, allowing rapid and flexible responses to changes in the environment, for example to allow blood coagulation by platelets. Integrins bind to extra-cellular proteins via short amino acid sequences, such as the R-G-D sequence motif (found in proteins such as fibronectin, laminin, or vitronectin)

IMMUNOGLOBULIN SUPERFAMILY
categorized as members of this superfamily based on shared structural features with immunoglobulins (also known as antibodies) Calcium independent Homophilic binding Proteins of the IgSF possess a structural domain known as an immunoglobulin (Ig) domain. contain about 70-110 amino acids and are categorized according to their size and function Ig-domains possess a characteristic Ig-fold, which has a sandwich-like structure formed by two sheets of anti-parallel beta strands.

NCAMs play important role in he differentiation of muscle. a single membrane-spanning segment and cytosolic segment that interacts with the cytoskeleton. gene mutation in L1-CAM causes various neuropathologies(e. In human.g.Among IgCAMs are neural CAMs. NCAMs comprises of extracellular region with five Ig repeats and two fibronectin type III repeats. mental retardation. congential hydrocephalus and spasticity) . glial and nerve cell. intercellular CAMs (ICAMs) which function in the movement of leukocytes into tissue and junction adhesion molecules (JAMs) which are present in tight junction.

Cell junctions are especially abundant in epithelial tissue.CELL JUNCTION Cell junction is a type of structure that exists within the tissue of a multi-cellular organism. . They consist of protein complexes and provide contact between neighboring cell or between a cell and the extra cellular matrix or they buildup the paracellular barrier of epithelia and control the paracellular transport.

COMMUNICATING JUNCTION: Mediates the passage of chemical or electrical signal from one interacting cell to its proteins . ANCHORING JUNCTION: Mechanically attaches cell (and their cytoskeletons) to their neighbors or to the extracellular matrix.CELL JUNCTION CAN BE CLASSIFIED INTO THREE FUNCTIONAL GROUP OCCULUDING JUNCTION: Junction that seal cell together in an epithelium in a way that prevents even small molecule from leaking from one side of the sheet to the other.

intermediate filament attachment sites i. gap junctions b. cell-matrix adherens junctions (e.1.. plasmodesmata (plants only) .sepate junction 2.Occluding junctions a.tight junctions b. actin filament attachment sites i. cell-cell adhesion (desmosomes) ii.g. Anchoring junctions a. Communicating junctions a.g.. cell-matrix adhesion (hemi-desmosomes) 3. chemical synapses c. adhesion belts) ii. cell-cell adherens junctions (e. focal contacts) b.

Although all tight junction are impermeable to macromolecule. the tight junctions between epithelial cells are thought to have both of these roles. Mixing of such protein and lipid occur if tight junction are disrupted by removing the extra cellular Ca2+ that is required for tight junction integrity. tight junction seal neighboring cells together so that if a low-molecular weight tracer is added to one side of an epithelium. . the epithelial cells lining the small intestine form a barrier that keeps the gut contents in the gut cavity. Second. their permeability to small molecule varies greatly in different epithelia. the lumen. it will generally not pass beyond the tight junction.OCCLUDING JUNCTION TIGHT JUNCTION: present in vertebrates. they function as barrier to the diffusion of some membrane proteins between apical and basolateral domains of the plasma membrane. first.

EACH TISSUE IS AN ORGANIZED ASSEMBLY OF CELLS HELD TOGETHER BY CELL-CELL ADHESIONS. CONNECTIVE TISSUES (GREEN). .SIMPLIFIED DRAWING OF A CROSS-SECTION THROUGH PART OF THE WALL OF THE INTESTINE. AND MUSCLE TISSUES (YELLOW). TUBELIKE ORGAN IS CONSTRUCTED FROM EPITHELIAL TISSUES (RED). OR BOTH. EXTRACELLULAR MATRIX. THIS LONG.

their permeability to small molecules varies greatly in different epithelia. .thus suggesting that strands acts as independent barrier to ion flow Major trans membrane protein are claudin and occludin and also ZO which is essential for formation of and function of tight junction. ability to restrict the passage of ions through the spaces between cell is found logarithmically with increasing number of strands in the network.Impermeable to macromolecule.

glucose is actively transported into the cell by Na+-driven glucose symports at the apical surface. This segregation permits a vectorial transfer of nutrients across the epithelial sheet from the gut lumen to the blood. and it diffuses out of the cell by facilitated diffusion mediated by glucose carriers in the basolateral membrane. Tight junctions are thought to confine the transport proteins to their appropriate membrane domains by acting as diffusion barriers within the lipid bilayer of the plasma membrane. In the example shown.Role of tight junction in transcellular protein: Transport proteins are confined to different regions of the plasma membrane in epithelial cells of the small intestine. these junctions also block the backflow of glucose from the basal side of the epithelium into the gut lumen .

allergies. and autism(impaired social interaction and communication and restricted and repetative behaviour) . inflammatory bowel disease. asthma. type-1 diabetes.DISORDER RELATED TO TIGHT JUNCTION Disruption of TJs leads to intestinal hyperpermeability (the so-called "leaky gut") which has been proposed by some researchers to involve a relationship with acute and chronic diseases such as systemic inflammatory response syndrome (SIRS frequently a response of the immune system to infection).

L. . they likewise form continuous band around each epithielial cell. Wood 1959 found in invertebrate tissues adhesion. This are main occluding junction in invertebrates regular in structure than a tight junction . communication septa walls regularly spaced cross bars 15-17 nm . sealing.SEPTATE JUNCTION Discovered by R. But their morphology is proteins that are arranged in parallel rows with a regular periodicity .

are seen as dense bars or septa. Cox. Gilula.Electron micrograph of a septate junction between two epithelial cells of a mollusk. seen in cross-section.B. (From N.]. which have a regular periodicity.P. ed. The rows. 1-29) . in Cell Communication [R. pp. The interacting plasma membranes. are connected by parallel rows of junctional proteins.

This observation suggests that the normal regulation of cell proliferation in epithelial tissue may depend in part on intra cellular signal that emanate from occluding junction. . Mutant flies that are deficient in this protein not only lack septate function but also develop epithelial tumors.A protein called Disc-large. which is required for the formation of septate junction in Drosophila is structurally related to the ZO protein found in vertebrate tight junction.

composed of two main classes of protein-Intra cellular anchor protein and Trans-membrane adhesion proteins.ANCHORING JUNCTION widely distributed in animal tissue and are most abundant in tissue that are subjected to serve mechanical stress such as heart. . muscle and epidermis.

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.Intracellular anchor protein: proteins form a distinct plaque on the cytoplasmic face of the plasma membrane and connect the junctional complex to either actin filaments or intermediate filaments. Trans-membrane adhesion protein : protein have a cytoplasmic tail that binds to one or more intracellular anchor protein and an extracellular domains that interacts with either the extracellular matrix or the extracellular domains of specific trans-membrane adhesion protein on another cell.

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Anchoring Junction occurs in two functionally different forms: 1. Adheren junction and desmosomes hold cell together and are formed by trans-membrane adhesion protein that belong to the cadherin family. 2. Focal adhesion and hemi-desmosomes bind cells to the extra cellular matrix and are formed by trans-membrane adhesion protein of the integrin family .

adherens junction 2. Intermedite filament attachment sites 1.Depending upon Cytoskeleton attachment sites anchoring junction is classified as A). Hemi-desmosomes . Desmosomes 2. Actin filament attachment sites 1. focal adhesion B).

The adhesion belt are directly opposed in adjacent epithielial cells with the interacting plasma membrane held together by the cadherins that serve here as transmembrane adhesion proteins. where they often form a continuous adhesion belt (zonula adherens) just below tight junction.ADHEREN JUNCTION An adhern junction is defined as cell junction whose cytoplasmic face is linked to the actin cytoskeleton . The assembly of the tight junction between epithelial cell seem to require the prior formation of adherens junction also block the formation of tight junction. In many non-epithelial tissues they take the form of small punctuate or streak like attachment that indirectly connect the cortical actin filament beneath the plasma membrane of two interacting cells. encircling each of the interacting cells in the sheet. .They can appear as band encircling the cell (zonula adherens) or as spots of attachment to the extracellular matrix (adhesion plaques ). But the prototypical examples of adheren junction occur in epithelia.

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they also grip the substratum at focal adhesion where bundle of actin filament terminate. -actinin. Likewise. . when cultured fibroblast migrates on an artificial substratum coated with extra-cellular matrix molecules.In this way muscle cells for example attach to their tendous at the myotendinous junction. while their intra-cellular domain bind indirectly to bundles of actin filament via the intra-cellular anchor protein talin. filamin and vinculin.FOCAL ADHESION Integrin mediated junction Enable cells to get hold on the extra-cellular matrix through integrins that link intra cellularly to actin filaments . the extracellular domains of trans-membrane integrin protein bind to a protein component of the extra-cellular matrix . At all such adhesion .

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Function as signal carriers (sensors). in which white blood cells migrate along the connective endothelium following cellular signals and to damaged biological tissue Also active signalling during cell motility to cell cycle . which inform the cell about the condition of the ECM and thus affect their behavior important role in the immune system.

DESMOSOMES Discovered by K. The junction has a dense cytoplasmic plaque composed of a complex of intra cellular anchor proteins (plakoglobin and desmoplakin) that are responsible for connecting the cytoskeleton to the trans-membrane adhesion proteins. The particular type of intermediate filament attached to the desmosomes depend on cell type: they are keratin filament in heart muscle cells . .R. Porter in 1954 Homophilic interaction between trans-membrane protein(Cadherin) Through desmosomes the intermediate filament of adjacent cell are linked into a net that extends throughout the many cell of a tissue .

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DSG3).(cadherin based protein desmoglein and desmocolin) .Found in muscle cells Blistering diseases such as Pemphigus vulgaris or Pemphigus foliaceus can be due to genetic defects in desmosomal proteins.(epithelial cells of skin) patients who suffer from autoimmune diseases characterized by skin and mucous membrane blistering produce autoantibodies against desmogleins 1 and 3 (DSG1. These two observations suggested that the loss of normal desmosome function could lead to tissue fragility disorders.

Instead of joining adjacent epithelial surface of an epithelial cell to underlying basal lamina. The extracellular domains of the integrins that mediate the adhesion bind to laminin protein in the basal lamina while an intracellular domain binds via an anchor protein (plectin) to keratin intermediate filaments. .HEMI-DESMOSOMES This are half-desmosomes resemble desmosomes morphologically and in connecting to intermediate filament and like desmosomes they act as rivets to distribute tensile or shearing forces through an epithelium .

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Genes encoding different components of hemidesmosomes have been found to be mutated in various forms of hereditary bullous skin disorders . The layers of the skin do not adhere properly and painful widespread blisters occur very easily.DISORDER DUE TO HEMI-DESMOSOMES Epidermolysis Bullosa is a set of genetically inherited conditions affecting 1 in 17. These can lead to increasing disfigurement. A fault in a gene causes the skin to be extremely fragile.000 of the population. disability and in the most severe forms death in early childhood.

vinculin. plakoglobin Adherens (cell-matrix) integrin extracellular matrix proteins actin filaments talin. vinculin. -actinin Hemidesmos ome integrin extracellular matrix (basal lamina) proteins intermediate filaments desmoplakinlike protein . actinin. plakoglobin Desmosome cadherin (desmogleins & desmocollins) cadherin in neighboring cell intermediate filaments desmoplakins.Table 19-2 Anchoring Junctions Junction Adherens (cell-cell) Transmembrane Linker Protein cadherin (E-cadherin) Extracellular Ligand cadherin in neighboring cell Intracellular Cytoskeletal Attachment actin filaments Some Intracellular Attachment Proteins catenins.

COMMUNICATING JUNCTION GAP JUNCTION Discovered by J.J. cells of cardiac and musclecommunication Are open channels allowing ions and small molecules to diffuse freely between Couples both the metabolic activities and the electric responses allows passages of some intracellular signalling molecules such as cAMP and Ca2+ . Revel & M. endothelial cell. Karnovsky in 1967. Found in animal cells including epithelial cell.P.

In (B) each gap junction is seen as a cluster of homogeneous intra-membrane particles associated exclusively with the cytoplasmic fracture face (P face) of the plasma membrane. in Cell Communication [R.Gap junctions as seen in the electron microscope.B. (From N.P. Thin-section (A) and freezefracture (B) electron micrographs of a large and a small gap junction between fibroblasts in culture. Gilula. 1-29) . Cox. pp. ed.].

products of intermediary metabolism and small intracellular signaling molecules can pass Gap junction composed of connexins. low-molecular weight precursors of cellular macromolecules.Permits the passage of molecules as large as 1. Innexins forms gap junction in invertebrates . a family of structurally related trans-membrane proteins which consist of 21 different human protein.2 nm in diameter (mammalian) and 2 nm in insects Molecules smaller than 1200 Da can pass but lager than that wont Thus ion.

. When fluorescent molecules of various sizes are injected into one of two cells coupled by gap junctions. molecules smaller than about 1000 daltons can pass into the other cell but larger molecules cannot.Determining the size of a gap-junction channel.

morphogenesis. and growth control in multicellular organisms .Vertebrate hexagonal particle consists of 12 connexin molecules: 6 of the molecules are arranged in connexon hemi-channel Hexagonal cylinder of one plasma membrane when joined to adjacent cell hemi-channel they form a continuous aqueous channel between the cell Homotypic connexon : single type of connexin Hetero-oligomeric connexon : two or more type of connexin plays a crucial role in the maintenance of homeostasis. cell differentiation.

THE APPOSED LIPID BILAYERS (RED) ARE PENETRATED BY PROTEIN ASSEMBLIES CALLED CONNEXONS (GREEN). EACH OF WHICH IS THOUGHT TO BE FORMED BY SIX IDENTICAL PROTEIN SUBUNITS (CALLED CONNEXINS).A MODEL OF A GAP JUNCTION. THE DRAWING SHOWS THE INTERACTING PLASMA MEMBRANES OF TWO ADJACENT CELLS. TWO CONNEXONS JOIN ACROSS THE INTERCELLULAR GAP TO FORM A CONTINUOUS AQUEOUS CHANNEL CONNECTING THE TWO CELLS. .

Gap junctions are not always open Opening & closing is regulated by changes in pH and Ca2+ concentration High Ca2+. Low pH ² closed Low Ca2+. high pH ² open .

Connexin 26 mutations have been found in hereditary nonsyndromic sensorineural deafness. including brain ischemia. Alzheimer's disease and epilepsy. gap junctions may be related to the degree of malignancy and metastasis . Connexin 43 knockout mice die shortly after delivery because of cardiac malformation. Neuronal gap junctions are involved in electrical coupling and may also contribute to the recovery of function after cell injury. Astrocytes are involved in the pathology of most neuronal disorders. In the pathology of brain tumors. an inherited peripheral demyelinating neuropathy.DISORDERS IN GAP JUNCTION Connexin 32 mutations cause X-linked CharcotMarie-Tooth disease.

. plasmodesmata function analogously to gap junction as means of direct communication between adjacent cells in tissues. Although distinct in structure. plasmodesma). Because of the rigidity of plant cell walls. specializes pectin-rich region of the cell wall called the middle lamella acts as a glue to hold adjacent cells together. In particular.PLASMODESMATA Plays a key role in plant development Adhesion between plant cells is mediated by their cell walls rather than by trans-membrane proteins. adjacent plant cell communicate with each other through cytoplasmic connection called plasmodesmata (singular. stable association between plant cells do not require the formation of cytoskeleton links such as those provided by the desmosomes and adherens junction of animal cells.

(A) THE CYTOPLASMIC CHANNELS OF PLASMODESMATA PIERCE THE PLANT CELL WALL AND CONNECT ALL CELLS IN A PLANT TOGETHER. IT USUALLY ALSO CONTAINS A FINE TUBULAR STRUCTURE (20-40NM). DERIVED FROM SMOOTH ENDOPLASMIC RETICULUM . (B) EACH PLASMODESMA IS LINED WITH PLASMA MEMBRANE COMMON TO TWO CONNECTED CELLS. THE DESMOTUBULE.PLASMODESMATA.

metabolic product and plant virus pass through plasmadesmota also membrane bound molecules . reverse inhibiting movement of molecules Molecules like protein.000 Da Increase conc. Extension of endoplasmic reticulum called as desmotubule Permits a passage of 10. of Ca2+ affects permeability. leaving a ring of surrounding cytoplasm through which ions and small molecules are able to pass freely between the cells.An extension of the smooth endoplasmic reticulum passes through the pore. nucleic acids.

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Serves as one-way communication devices. who argued. Ramóny Cajal. on the basis of his own observations of reflex responses and the studies of the great Spanish anatomist.CHEMICAL SYNAPSES The term was introduced by British neurophysiologist Charles Sherrington. transmitting information in one direction only Consist of pre-synaptic cell which transmits information to post-synaptic cell which recieves information Pre-synaptic cell and post-synaptic cell are are separated by minute gap called synaptic cleft Neurotransmitter act as median for transmission .

Cytoplasm of pre-synaptic cell is full of small vesicles When an action potential arrives in the terminal it stimulates the opening of calcium channels in the terminal membrane. calcium ions flood into the cell and cause the synaptic vesicles to release their contents into the synaptic cleft. . As a consequence.

adenosine. NA). glycine Monoamines and other biogenic amines: dopamine (DA). epinephrine (adrenaline). histamine. anandamide.Binding of neurotransmitter molecule produces a change in the three-dimensional shape of the receptors that opens a tiny intrinsic pore in the protein. aminobutyric acid (GABA). 5-HT). NE. nitric oxide . norepinephrine (noradrenaline. D-serine. melatonin Others: acetylcholine (ACh). serotonin (SE. aspartate. Major neurotransmitters: Amino acids: glutamate.

DISORDERS RELATED TO CHEMICAL SYNAPSES the inherited neuromuscular disorder. Epilepsy : decrease in the efficiency of inhibitory transmission in the brain. depression and schizophrenia. leading to overexcitability of networks of neurons. There is some evidence that the major psychiatric conditions. occurs when the body produces antibodies to the acetylcholine receptors on muscle fibres. . act as neurotransmitters. involve disorders of synapses in which serotonin and dopamine. respectively. myasthenia gravis(deficency of enzyme that breaks down acetylcholine).

cadherins and immunglobulin superfamily Cell Junction gap junction. septate junction anchoring junction (adherens and focal ) and (desmosomes and hemi-desmosomes) Gap junction plasmadesmota and chemical synapses . selectin.SUMMARY What is cell adhesion and its role Types of cell adhesion Cell adhesion and its molecules (CAM) integrin.

Karen Hoplein. Geoffery M. Garland science publications. ´The Cell A Molecular Approachµ. page no: 258-268 .BIBLOGRAPHY Bruce Alberts. (2004). Ed: 3. Julian Lewis. Cooper. ASM Press and Sinauer Associates. Keith Roberts and Peter Walter. Inc. Ed:4. Alexander Johnson. Ed:4. Robert E. Dennis Bray. Hausman (2009). Martin Raff. Gerald Karp (2002) ´Cell and Molecular Biology Concept and Experimentµ. New York. ´Molecular biology of the cellµ .

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