1. Tight junctions, desmosomes, and focal adhesions are the three main types of intercellular junctions that were discussed. 2. Tight junctions form a seal around cells to control passage between cells and maintain cell polarity. Desmosomes anchor cells together through intermediate filaments to resist mechanical stress. Focal adhesions link the actin cytoskeleton to the extracellular matrix through integrin proteins. 3. Diseases can arise from defects in the proteins that form intercellular junctions, disrupting the barriers and cell-cell or cell-matrix connections they provide.

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2. INTERCELLULAR JUNCTIONS
HEALTH AND DISEASE
2
By
Dr.S.Aafiya Reshma
IIyr Post Graduate

3. SYNOPSIS
• INTRODUCTION
• DEFINITION
• CLASSIFICATION
Tight junctions
Adhesive junctions
Gap junctions
• Diseases associated
• references
3

4. INTRODUCTION
4

5. INTERCELLULAR JUNCTIONS
• When cells come into contact with one another and
sometimes with the extracellular matrix, specialized junctions
may form at specific sites on the contacting cell membranes.
• They are termed as Cell Junctions
Occluding Junction
Communicating Junction
Anchoring Junction

6. CLASSIFICATION
INTERCELLULAR JUNCTIONS
OCCLUDING
JUNCTIONS
TIGHT
JUNCTIONS(Zonula
Occludens)
COMMUNICATING
JUNCTIONS
GAP
JUNCTIONS
ANCHORING(Adhesive
Junctions)
CELL-TO-
CELL
ZONULA
ADHERENS
MACULA
ADHERENS
(Desmosomes)
CELL-TO-
MATRIX
FOCAL
ADHESIONS
HEMIDESMOSOMES
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7. Tight Junction

8. TIGHT JUNCTIONS
• Epithelial and endothelial barrier integrity essential for homeostasis
is maintained by cellular boarder structure known as TIGHT
JUNCTIONS.
• It is also known as ZONULA OCCLUDENS.
• ZONULA means a junction that completely encircles the cell.
• The opposing cell membranes are held together by the presence of
transmembrane adhesive proteins arranged in anastomosing strands
that encircle the cell.
• The transmembrane proteins include
• Occludin
• Members of the claudin family
• Junctional adhesion molecule(JAM)
• Here the membrane of the two cells become opposed and the outer
layer of the membrane fuses. It obliterates the space between the
cells. It is seen typically in the apical margins of the cell.
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ON MOLECULAR BASIS, it has 3 components
TRANSMEMBRANE ADHESIVE PROTEINS
CYTOPLASMIC ADAPTER PROTEIN
CYTOSKELETAL FILAMENT
• Transmembrane adhesive proteins interact homotypically with the same proteins on the
adjacent cell.

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CLAUDIN:
• Claudins were first named in 1988 by Japanese
researchers Mikio Furuse and Sjoichiro Tsukita at
Kyoto University. They are found in many organisms,
ranging from nematodes to human beings.
• The name claudin comes from Latin word claudere ("to
close"), suggesting the barrier role of these proteins.
• They are understood to be the backbone of tight
junctions and play a significant role in the tight
junction's ability to seal the paracellular space.
TRANSMEMBRANE ADHESIVE PROTEINS

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Tissue Predominate claudin species
Kidney
Glomerulus -1, 2, 6
Proximal tubule -2, 6, 9, 10, 17
Thin limb -4, 7, 8, 10
Thick limb -10, 14, 16, 19
Collecting duct -3, 4, 7, 8, 10, 18
Lungs
Conducting airways -1, 3, 4, 8
Respiratory airways -3, 4, 18
Gastrointestinal tract
Stomach -2, 3, 4, 10, 13, 18
Small intestine -3, 4, 5, 18
Intestinal crypt -2, 10, 15
Intestinal villi -3, 4, 7, 8, 13, 23
Colon -3, 4, 7, 8
Endothelium -3, 5, 12
Claudins expressed in selected tissues and tissue
segments.
REFERENCE: Hou J (2014) The kidney tight junction (review). Int J Mol Med 34:1451–1457

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OCCLUDIN:
• Described for the first time in 1993 by Shoichiro Tsukita
• It is the main component of the tight junctions along with the members of the
claudin family
• It play a main role in cellular structure and barrier function.
ROLE OF OCCLUDIN IN CANCER:
 Mutation or absence of occludin increases epithelial leakiness which is an
important barrier in preventing metastasis of cancer.
 Loss of occludin or abnormal expression of occludin has been shown to cause
increased invasion, reduced adhesion and significantly reduced tight junction
function in breast cancer tissues.
 Furthermore, patients with metastatic disease displayed significantly lower levels of
occludin suggesting that the loss of occludin and thereby loss of tight junction
integrity is important in metastatic development of breast cancer.
REFERENCE:
Martin TA, Mansel RE, Jiang WG (November 2010). "Loss of occludin leads to the progression of human
breast cancer". International Journal of Molecular Medicine. 26 (5): 723–34.

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JUNCTIONAL ADHESION MOLECULES(JAM):
• Junctional Adhesion Molecules (JAM) are part of the immunoglobulin superfamily and is
expressed in variety of tissues such as leukocytes,platelets, epithelial and endothelial
cells.
• JAMs are usually around 40kDa in size.
• Their structure differs from that of the other integral membrane proteins in that they
only have one transmembrane domain instead of four.
• It helps to regulate the paracellular pathway function of tight junctions and is also
involved in helping to maintain cell polarity.
REFERENCE:Luissint, Anny-Claude; Artus, Cédric; Glacial, Fabienne; Ganeshamoorthy, Kayathiri; Couraud,
Pierre-Olivier (2012-11-09). "Tight junctions at the blood brain barrier: physiological architecture and disease-
associated dysregulation". Fluids and Barriers of the CNS. 9 (1): 23

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TYPES:
JAM-1:
• JAM-1 was the first of the junctional adhesion molecules to be discovered, and is located in the
tight junctions of both epithelial and endothelial cells.
• AM-1interacts with cells in a homophilic manner in order to preserve the structure of the
junction while moderating its permeability.
• JAM-1 also plays a significant role in many different cellular functions, including being both
a reovirus receptor and a platelet receptor
JAM-2:
• JAM-2 also is a member of the immunoglobulin superfamily.
• JAM-2 has also shown to act as a ligand for many immune cells, and plays a role in lymphocyte
attraction to specific organs.
JAM-3:
• JAM-3 functions similarly to JAM-2 as it is localized around the tight junctions of epithelial and
endothelial cells, but has been shown to be unable to adhere to leukocytes in the manner that
other JAMs can.

15. FUNCTIONS:
CELL MOTILITY:
• JAM-1 and JAM-3 allow leukocytes to migrate into connective tissue by
freeing polymorphonuclear leukocytes from entrapment in endothelial cells
and basement membranes.
• In the absence of JAM-1, these leukocytes cannot moderate β1 integrin endocytosis,
and cannot be effectively expressed on the surface of the cell.
CELL POLARITY:
• JAM-1 and JAM-3 have significant roles in regulating cell polarity through their
interactions with cell polarity proteins
• JAM-3 has also shown to affect cell polarity in spermatids by regulating the
localization of cytosolic polarity.
CELL PROLIFERATION:
• Some organs that require high rates of cellular turnover are the small intestine and
the colon. JAM-1 has been shown to regulate the proliferation of cells in the colon.
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16. CYTOPLASMIC ADAPTER PROTEINS
• They associate with the intracellular transmembrane proteins
• These include:
 Cell polarity related proteins
 Vesicular transport related proteins
 Kinases
 Transcription factor
 Tumor suppressor protein.
• In addition, some of the cytoplasmic proteins of the junction bind to
the actin filaments.
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FUNCTIONS OF TIGHT JUNCTION:
• They hold cells together.
• It controls the passage of material through the
intercellular spaces and prevents the passage of
molecules and ions through the space between
cells.
• Tight junctions help to maintain the apicobasal
polarity of cells by preventing the lateral
diffusion of integral membrane proteins
between the apical and lateral/basal surfaces,
allowing the specialized functions of each
surface to be preserved.
• This allows polarized transcellular transport
and specialised functions of apical and
basolateral membranes.

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• Tight junctions seal adjacent epithelial cells in
a narrow band just beneath their apical
surface
• Tightly aligned rows of tight junction proteins
serve to stitch the membrane together
effectively sealing the association between
adjacent cells.
• This serves to block the movement of
materials through intercellular space.

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Adhesive Junction

20. ADHESIVE JUNCTION
• Adhesive junction hold cells together or anchor cells to the extracellular matrix.
• They occur at cell-cell junctions in epithelial tissues, usually more basal than tight junctions.
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• Cells adhere to each other and to the extracellular matrix through cell surface proteins called CELL
ADHESION MOLECULES(CAMs)
• CAMs are proteins located on the cell surface involved in binding with other cells or with
extracellular matrix in the process called CELL ADHESION.
• These proteins are typically transmembrane receptors and are composed of three domain:
• An intracellular domain that interacts with the cytoskeleton,
• A transmembrane protein
• An extracellular domain that interacts either with other CAMs of the same kind or with other
CAMs or the extracellular matrix.
CLASSIFICATION OF CELL ADHESION MOLECULES:
 Cadherins
 Ig superfamily CAMs
 Selectins
 Integrins
 Mucins

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CADHERINS:
 The cadherins are Calcium dependent adhesion molecule which plays
important role in cell adhesion by forming desmosomes.
 SUB CLASSES:
 Neural(N)-Cadherin
 Placental(P)-cadherin
 Epithelia(E)-Cadherin
 They exhibit homophilic adhesion
Ig SUPER FAMILY CAMs:
 The Ig Superfamily CAMs are Calcium independent trans membrane
glycoproteins
 Members include: ICAM,VCAM-1, PECAM-1,NCAM.
 It functions by both homophilic and heterophilic binding

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SELECTINS:
• The selectins are a family of Divalent Cation Dependent Glycoproteins
• They are carbohydrate –binding proteins
• Members include:
• Endothelial(E)-selectin
• Leukocyte(L)- selectin
• Platelet(P)-selectin
• It plays an important role in many host defense mechanisms.
INTEGRINS:
• Integrins are diverse group and large group of heterodimeric glycoproteins
• Integrins participate in cell-cell adhesion, in binding and interaction of cells
with components of the extracellular matrix such as fibronectin
MUCIN:
• The mucins are the group of serine and threonine rich protein
and Hydroxyproline enabling post translational O-glycosylation
• Their extended structure allows them to present sulphated
carbohydrate moieties as binding site for selectins

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CELL ADHESION MOLECULES

25. CELL-CELL ADHESIVE JUNCTION
• In cell – cell adhesive junction , the principal transmembrane proteins are the members of
the CADHERIN family
• The cytoplasmic adapter proteins are members of the CATENIN family.
• Catenins are proteins found in complexes with cadherin cell adhesion molecules of animal
cells.
TYPES OF CATENIN:
Alpha catenin
Beta catenin
Delta catenin
Gamma catenin
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26. ZONULAADHERENS
Cadherin family member: E-Cadherin
Cytoplasmic adapter proteins: α catenin and β catenin
Cytoskeletal component: Actin filament
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Other transmembrane adhesive proteins present in adhesive junctions are-
NECTIN- A member of immunoglobulin superfamily.
 Nectin has an important role during junction formation, establishing the initial
adhesion site and recruiting e cadherin and other proteins to the junction.
Other cytoplasmic proteins associated with the zonula adherens include:
 p120 catenin: a signaling molecule associated with E cadherin that is
important in stabilizing the junction.
 Afadin: which links nectin to the nectin cytoskeleton
 Vinuculin and α actinin: which are actin binding proteins
 Ponsin: which links afadin and vinculin.

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29. MACULA
ADHERENS(DESMOSOMES)
• Desmosomes are essential adhesion structure in most epithelia that link the
intermediate filament network of one cell to its neighbours thereby forming a
strong bond.
• It is also known as Macula adherens junction or spot desmosomes.
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STRUCTURE OF DESMOSOMES:
Desmosome consists of three components
 The transmembrane molecules
 The plaque molecules or cytoplasmic adapter protein
 Intermediate filament(IF)
Extracellularly, desmosomes are separated by a 25-30nm
space
The interaction of the transmembrane proteins with those
from the adjacent cells result in a dense line in the middle
of the intercellular space at the desmosome.

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In desmosomes:
• CADHERINS: desmoglein
desmocollin
The interaction of these transmembrane proteins with those from the
adjacent cell result in a dense line in the middle of the intercellular
space at the desmosome.
• CATENINS : desmoplakin
plakoglobin
plakophilin
• The catenin forms an electron dense plaque on the cytoplasmic
side of the desmosome.
• This plaque serves as an attachment site for the cytoskeleton
component, which in the case of the desmosome are intermediate
filaments.
.

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FUNCTIONS OF DESMOSOMES:
 Desmosome creates a transcellular network throughout a tissue that resist
forces of mechanical stress. Hence found in stratified squamous epithelia and
myocardium subjected to constant stress.
 The desmosome- intermediate filament complex impart tensile strength and
resilience to the epithelium.
ROLE IN Cancer:
• Downregulation of PKP3 by RNAi in epithelial cells lines yielded three
notable hallmarks of oncogenic transformation and invasion – decreased
desmosomal size and cell-cell adhesion, and increased cell migration

33. CELL MATRIX JUNCTION
33
Cell matrix junction
have a structural
organization similar to
that of cell –cell
adhesive junction.

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FOCALADHESIONS:
• Focal adhesions link the actin-rich cytoskeleton of cells
with the extracellular matrix to mediate cell adhesion and
migration, mechnaosensing, and intracellular signaling
events.
• It is highly complex process that requires assembly of
vinuculin, talin, paxillin, tensin, zyxin, focal adhesion
kinase, α-actinin.
• The transmembrane component is a member of the
INTEGRIN family of adhesion molecules .
• The cytoplasmic adapter proteins, which include the actin
binding proteins are α-actinin, vinuculin and talin, link the
transmembrane integrins to the actin cytoskeleton.
• Binding of the integrin to COLLAGEN, LAMININ,
FIBRONECTIN,and other extracellular matrix proteins
results in recruitment and remodeling of the actin
cytoskeleton.

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HEMIDESMOSOMES:
 Hemidesmosomes are specialized junctional complexes that
contribute to the attachment of epithelial cell to the underlying
Basement Membrane in stratified and other complex epithelia.
 Hemidesmosomes are very small stud or rivet like structures on
the inner basal surface of keratinocytes in the epidermis of the
skin.
 While desmosomes link two cells together , hemidesmosomes
attach one cell to the extracellular matrix
 Rather than using cadherins, hemidesmosomes use integrins cell
adhesion proteins
 Hemidesmosomes are asymmetrical and are found in epithelial
cells connecting the basal face to other cells.

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Three classes of proteins are involved in the molecular organization of this complex:
A. Cytoplasmic plaque proteins
B. Transmembrane proteins
C. Basement membrane associated proteins
The transmembrane adhesive proteins are integrin α6β4, which binds specifically to the basal
lamina glycoprotein and collagen XVII (BP180).
• The cytoplasmic adapter proteins, bullous pemhigoid antigen230(BP230) and plectin, form a
dense plaque on the cytoplasmic surface of the hemidesmosome which function as an attachment
site for intermediate filaments.

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FUNCTIONS:
 These multiprotein complexes determine cell –stromal coherence (plaque
componentsBP230 and Plectin connect intermediate filament to plasma
membrane)
 Helps in spatial organization of cell.
 Important for tissue architecture (integrin α6β4 and BP180 involved in the
assembly of hemidesmosomes and mediate cell adhesion).
 It plays an important role in tissue morphogenesis and wound healing
 It serves a signalling devices integrin α6β4 integrin.

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Gap Junctions

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• Gap junctions are plaque like regions of the cell
membrane where the intercellular space narrows to 2
to 3nm.
• The transmembrane proteins are the CONNEXIN
family
• They form aqueous channels between the cytoplasm
of the adjacent cells.
• Six connexin molecule forms a connexon which has
a central channel approximately 2nm in diameter.
• The connexons in one cell pair with connexons in the
adjacent cell to create a patent channel.
• Small molecules, such as ions and signaling
molecules can move readily from one cell to another.

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FUNCTIONS:
• The diameter of the connexon is normally about 2nm, which permits the
passage of ions, sugars, amino acids and other solutes with molecular weights
upto about 1000 Dalton.
• It function as suppressors of somatic cell mutations- loss of a critical
metabolic enzyme or ion channel in one cell compensated by its neighbours.
• They are particularly important in cardiac muscle- the signal to contract is
passed efficiently through gap junctions, allowing the heart muscle cells to
contract.
• A gap junction located in neurons referred to as an electrical synapse are
important in neurotransmitter release.

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INTERCELLULAR JUNCTIONS IN DISEASE

46. TIGHT JUNCTION
• The organization and expression of TJ proteins drastically change in
salivary glands in SS.
• In this regard, occludin and ZO-1 are downregulated, whereas claudin-1
and claudin-4 are overexpressed in salivary glands of SS patients.
• In addition, these claudins move from the apical to the basolateral side of
acinar cells in minor salivary glands (Ewert et al., 2010).
• The release of pro-inflammatory cytokines disrupts the integrity of TJs. It
has been shown that IFN-γ and TNF-α compromise the barrier function of
TJs, which is associated with a drop in claudin-1 production (Baker et al.,
2008).
• Thus, the disruption of TJ integrity in SS is closely linked to the secretion
of inflammatory mediators.
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47. DISEASES OF TIGHT JUNCTION
• TJs are involved in carcinogenesis in the oral cavity, including oral
squamous cell carcinoma (OSCC).
• The loss of TJ proteins can induce dedifferentiation and promotes cancer
progression.
• This is in line with the findings of several studies showing carcinogenesis,
tumor recurrence and poor survival in patients with loss of TJ molecules in
different cancer types (Martin et al., 2010).
• However, other studies show that overexpression of TJ proteins, in
particular JAM and claudins, is linked to tumor growth.
• Hence, it has been suggested that increased TJ protein expression, rather
than their loss, facilitates carcinogenesis (Leech et al., 2015).
• Overexpression of claudin-1 has been observed in advanced stages of OSCC,
coinciding with angiolymphatic and perineural tumor invasion (dos Reis et
al., 2008).
47

48. • This is associated with activation of matrix metalloproteases (MMPs) and
therefore increased cleavage of extracellular matrix components.
• Moreover, the activation of MMPs and OSCC invasion become more
manifested upon suppression of claudin-1 production (Oku et al., 2006).
• CAR also has a critical role in the progression of OSCC by promoting cancer
cell growth and survival, while negatively affecting the apoptotic machinery.
• The latter is mediated via the specific interaction of CAR with Rho-associated
protein kinase and its subsequent inhibition that accelerates cell-cell
adhesion required for cancer cell growth.
• OSCC growth is reduced because of cell dissociation in the absence of CAR
expression (Saito et al., 2014).
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49. GAP JUNCTION
• Normal epithelial cells show Cx43 and Cx26 production, whereas OSCC cells
only express Cx43 (Frank et al., 2006).
• In fact, Cx43 has been proposed as a prognostic biomarker in OSCC
associated with poor survival (Brockmeyer et al., 2014).
• GJs exert different functions depending on the OSCC stage.
• Cx proteins regulate cell cycling by affecting the transcription of genes coding
for cyclins and cyclin-dependent kinases (Cronier et al., 2008).
• The loss of GJs typically enhances cell proliferation. Cx proteins may promote
attachment of cancerous cells to the stroma during tumor metastasis.
• Cx26 overexpression has been detected in tissue specimens of OSCC and
lymph node metastasis (Villaret et al., 2000).
• Unlike Cx43, Cx26 and Cx45 have been reported to have no prognostic value
in OSCC (Brockmeyer et al., 2014).
49

50. ANCHORING JUNCTION
• Any disturbance in the function of cadherin-consisting AJs results in several
human pathologies, such as cancer, inflammation and auto-immune disorders
(Wheelock and Johnson, 2003; Garrod et al., 2002).
• Aberrant expression of E-cadherin is associated with tumor metastasis and
invasiveness, and might serve as a prominent prognostic marker in cancer
(Moh and Shen, 2009).
• . The infection in periodontitis destroys the supporting periodontal tissue
through the release of proteolytic enzymes and inflammatory cytokines from
immune cells (Ebersole et al., 2013).
• The pocket formation, inflammation and the activity of osteoclasts are
hallmarks of periodontitis and highly depend on cell-cell junctions (Wan et al.,
2018b).
• It has been suggested that developmental remnants of the junctional
epithelium are the sources of non-keratinizing squamous epithelial cells in the
pocket.
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51. PEMPHIGUS:
• The presence of auto-antibodies directed against Dsg1 causes the generation of blisters in
the upper granular layers of the epidermis in pemphigus foliaceus.
• Pemphigus vulgaris is associated with oral lesions and is accompanied by the production
of Dsg3 auto-antibodies (Wan et al., 2018a).
ORAL LICHEN PLANUS:
• Oral lichen planus, which is characterized by an epidermal auto-immune attack, is
considered as an idiopathic inflammatory disorder.
• Chronic immune damage to keratinocytes located in the oral mucosa is thought to play a
key role in this disease (Thornhill, 2001).
• High concentrations of auto-antibodies against Dsg1 and Dsg3 have been observed in
erosive lichen planus patients (Lukač et al., 2006).
• Furthermore, it has been reported that disruption of hemi-desmosomes results in the
degeneration of basal keratinocytes and the deregulation of basal membranes, which
produces weakness in epithelial connective tissues of the oral cavity in lichen planus
(Lucchese, 2015).
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52. PEMPHIGOID:
• Mucosal pemphigoid, an auto-immune blistering disorder, is caused by the
formation of auto-antibodies against the structural components of hemi-
desmosomes and/or basement membrane zone (Scully and Muzio, 2008).
• The generated auto-antibodies deregulate the binding of basal keratinocytes to
the underlying basement membrane, leading to the occurrence of sub-
epithelial blisters (Schmidt and Zillikens, 2013).
• Auto-antibodies against integrin α6β4, BP180, BP230, laminin and their
subunits might be produced (Feller et al., 2017).
• This disease is commonly initiated in the mouth and is occasionally restricted
to the oral mucosa (Kasperkiewicz et al., 2012).
• The rupture of sub-epithelial blisters results in the rapid formation of
fibrinous pseudomembranes around the painful ulcers
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53. • Odontoblasts become active secretory resources and tubuli are calcified
during dental caries(Tziafas et al., 2000).
• While odontoblasts surround the carious lesion, Cx43 expression is
increased in adult dental tissue, thus suggesting a role for GJs in
hypercalcification.
• The increased expression of Cx43 in osteoclasts and periodontal ligament
cells in the compression zone has been demonstrated in an orthodontic force
model.
• Furthermore, the tension zones of the periodontal ligament show increased
Cx43 levels in osteoblasts and osteocytes.
• Therefore, coordination of alveolar bone remodeling might be depending on
the activity of Cx43.
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55. 55
1. Ten Cate’s Oral Histology_ Development, Structure, and Function
2. Orban’s Oral Histology and Embryology
3. Norimasa Sawada · Masaki Murata · Keisuke Kikuchi Makoto Osanai · Hirotoshi Tobioka ·
Takashi Kojima Hideki Chiba Tight junctions and human diseases Med Electron Microsc (2003)
36:147–156 © The Clinical Electron Microscopy Society of Japan 2003 DOI 10.1007/s00795-
003-0219-
4. Tight Junction Proteins and Signaling Pathways in Cancer and Inflammation: A Functional
CrosstalkAjaz A. Bhat1*, Srijayaprakash Uppada2, Iman W. Achkar3, Sheema Hashem1, Santosh
K. Yadav1, Muralitharan Shanmugakonar4, Hamda A. Al-Naemi4,5, Mohammad
Haris1,4 and Shahab Uddin3 https://doi.org/10.3389/fphys.2018.01942
5. Cell junctions and oral health,Mohammad Samiei, Elham Ahmadian, Aziz
Eftekhari, Mohammad Ali Eghbal, Fereshte Rezaie, and Mathieu Vinken EXCLI J. 2019; 18:
317–330.
REFERENCE:

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