INTERCELLULAR JUNCTIONS
Post graduate department of physiology
Presenter - Dr Samia Mearaj
PG 1st year
Moderator - Dr Shabir
OVERVIEW
Introduction
History
Classification
Different junctions and their functions
Cell Adhesion Molecules
Recent advances
Summary
INTRODUCTION
Cell junctions are proteinaceous structures that physically hold two
surfaces together. Cell junctions aid in communication and
structural support and act as barriers. They can be broadly split
into two groups:
1) 1) junctions that fasten the cells to one another and to
surrounding tissues endowing strength and stability
2) AND
1. 2) junctions that permit the transfer of ions and other molecules
from one cell to another
HISTORY
1. Investigation of junctions began when microscopists and physiologists
recognized that epithelial and muscle cells adhere to each other and
underlying extracellular matrix. The physical basis of these
interactions became clear during the 1960s, when electron
micrographs of thin sections of vertebrate tissues revealed four types
of intercellular junctions.
2. Cell-cell junctions in the mammary gland were first described in detail
by Dorothy Pitelka in a series of classic electron micrographs.
• In the late 1970s, the ultrastructural organization and specificities of
CLASSIFICATION
• Cell junctions can be classified into three functional groups:
• I. Occluding junctions :
• They seal cells together in an epithelium in a way that prevents even
small molecules from leaking from one side of the sheet to the other.
• 2.Anchoring junctions :
• They mechanically attach cells (and their cytoskeletons) to their
neighbors or to the extracellular matrix
• 3.Communicating junctions :
• They mediate the passage of chemical or electrical signals from one
interacting cell to its neighbor.
TIGHT JUNCTIONS
Tight junctions, also known as zona occludens, are intercellular
adhesion complexes in epithelia and endothelia such as the
intestinal mucosa, the walls of the renal tubules, and the choroid
plexus.
They characteristically surround the apical margins that control
paracellular transport.
They are made up of ridges—half from one cell and half from the
other—which adhere so strongly at cell junctions that they
almost obliterate the space between the cells.
PROTEINS INVOLVED
Two types:
1. Tight junction membrane proteins or integral membrane proteins,
such as occludin, claudin and junctional adhesion molecules (JAMs).
• 2. Scaffold (framework or platform) proteins or peripheral
membrane proteins or cytoplasmic plaque proteins such as
cingulin, symplekin and Z01, 2, 3.
THEIR FUNCTION
Tight junctions permit the passage of ions, solute and intracellular
signaling molecules in between adjacent cells (paracellular pathway)
and the degree of this “leakiness” varies, depending in part on the
protein makeup of the tight junction.
In addition, tight junctions prevent the movement of proteins in the
plane of the membrane, helping maintain the different distribution of
transporters and channels in the apical and basolateral cell membranes
that make transport across epithelia possible.
They are also important to endothelial barrier function and endothelium-
dependent vasodilation.
APPLIED PHYSIOLOGY
• Common bacteria that affect tight junctions include several
gastrointestinal pathogens like Samonella, Helicobacter pylori, and
pathogenic Escherichia coli. These target the tight junctions of the
intestinal epithelium in different ways, such as using the
junction proteins for their attachment to the tissue, which facilitates
their passage to the interior cells, or just destroys them to access the
underlying cells.
ANCHORING JUNCTIONS
Anchoring junctions occur in two functionally different forms:
1.Adherens junctions and desmosomes hold cells together
and are formed by transmembrane adhesion proteins that
belong to the cadherin family.
2.Focal adhesions and hemidesmosomes bind cells to
the extracellular matrix and are formed by transmembrane
adhesion proteins of the integrin family
INVOLVED PROTIENS
• They are composed of two main classes of proteins
• Intracellular anchor 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.
• Transmembrane adhesion proteins have a cytoplasmic tail that binds to
one or more intracellular anchor proteins and an extracellular domain.
ADHERENCE JUNCTIONS
• Adherens junctions (AJs) are cell-cell adhesion complexes that are
continuously assembled and disassembled, allowing cells within a
tissue to respond to forces, biochemical signals and structural
changes in their microenvironment. The events leading up
to adherens junction formation ultimately result in the recruitment
of transmembrane cadherins, catenins (beta-catenins, alpha-
catenins) and cytoskeletal adaptor proteins that form the primary
architecture of adherens junctions.
PROTEINS INVOLVED
• The core of the Adherens junction includes
interactions among transmembrane
glycoproteins of the classical cadherin
superfamily, such as E-cadherin, and the
catenin family members including p120-
catenin, β-catenin, and α-catenin.
APPLIED PHYSIOLOGY
• Disruption of the adherens junctions or defects
in the associated proteins are associated with a
variety of diseases including inflammatory
bowel disease, disorders of the skin and hair
and cancer
Desmosomes are patches characterized
by apposed thickenings of the
membranes of two adjacent cells.
Attached to the thickened area in each
cell are intermediate filaments, some
DESMOSOMES running parallel to the membrane and
others radiating away from it.
Between the two membrane thickenings,
the intercellular space contains
filamentous material that includes
cadherins and the extracellular portions
of several other transmembrane
proteins.
PROTEINS INVOLVED
• Three major gene families encode desmosomal
proteins. Desmosomal cadherins, comprising two
subtypes called desmogleins and desmocollins,
are a subfamily of the cadherin superfamily that
mediate calcium-dependent cell–cell adhesion
• In humans, four genes encode desmogleins (Dsg1-
4) and three genes encode desmocollins (Dsc1-3)
APPLIED PHYSIOLOGY
• In pemphigus foliaceus, autoantibodies (IgG)
targeting desmoglein Dsg1 are generated,
resulting in superficial blisters in the granular
layer of the epidermis. In pemphigus vulgaris,
IgG targeting both Dsg3 and Dsg1 are
produced, resulting in deep epidermal blisters
and oral erosions
Hemidesmosomes look like half-
desmosomes that attach cells to
the underlying basal lamina and are
connected intracellularly to
intermediate filaments.
HEMIDESMOSOM
However, they contain integrins
ES rather than cadherins.
They are labile structures
associated with actin filaments
inside the cell, and they play an
important role in cell movement.
APPLIED PHYSIOLOGY
• Bullous pemphigoid (BP) is the most common
acquired disease of hemidesmosomes. Two
proteins, BP180 and BP230, have been
identified as primary targets of autoantibodies
in BP.
FOCAL ADHESIONS
Focal adhesion, also called mechanical attachment, mediates
the connection between the cell to the extracellular matrix. It
forms through the interaction between actin and integrin. Focal
adhesion promotes cell spreading and migration. And it is also
involved in cell signalling. Integrins are the core proteins of
focal adhesions, mediating the mutual recognition and
adhesion between cells and extracellular matrices. So integrins
serve as a messenger for the connection between external
cells and the internal structure of cells.
GAP JUNCTIONS
• The intercellular space is up to 4 nm at gap junctions. Here, units
called connexons in the membrane of each cell are lined up with one
another to form the gap junction
• Each connexon is made up of six protein subunits called connexins
• They surround a channel that, when lined up with the channel in the
corresponding connexon in the adjacent cell, permits substances to
pass between the cells with out entering the ECF.
• The pore diameter in the channel is estimated between 0.8 and 1.4
nm, which permits the passage of ions, sugars, amino acids, and
other solutes with molecular weights up to about 1000 Da
• Gap junctions thus permit the rapid propagation of electrical activity
from cell to cell as well as the exchange of various chemical
messengers and intracellular signalling molecules.
• At least 20 different genes code for connexins in humans, and
mutations in these genes can lead to diseases that are highly
selective in terms of the tissues involved and the type of
communication between cells produced.
THEIR FUNCTIONS
• Diameter of the channel in the gap junction is
about 1.5 to 3 nm. So, the channel permits the
passage of glucose, amino acids, ions and
other substances, which have a molecular
weight less than 1,000.
• It helps in the exchange of chemical
messengers and hormones between the cell.
APPLIED PHYSIOLOGY
• In humans, there are about 20 different genes
that code for connexin proteins. Mutation of
these genes results in diseases that are
specific for tissues. Few examples are:
• Deafness
• Keratoderma
• Cataract
CELL ADHESION MOLECULES
Cell adhesion molecules (CAMs) are surface glycoproteins present on the
cell membrane. They are important for binding to other cells as well as to
the extracellular matrix where they bind to laminins . Apart from holding
the tissues together, CAMs have important roles in inflammation and
wound healing, embryonic development, axonal growth, and tumor
metastasis.
• There are four important groups of CAMs:
• Selectins are required for capturing the free flowing neutrophils
and making them roll along the endothelial wall.
• Integrins and the IgG superfamily immunoglobulins are present
on the endothelium. They bring about a firm adhesion of the
neutrophil with the endothelium.
• Neutrophilic migration through the endothelial wall (diapedesis)
requires dissociation of intercellular cadherin contacts.
FUNCTIONS
Cells are attached to the basal lamina and to each other by
CAMs that are prominent parts of the intercellular connections
described below. The unique structural and signaling functions of
these adhesion proteins have been found to be important in
embryonic development and formation of the nervous system
and other tissues, in holding tissues together in adults, in
inflammation and wound healing, and in the metastasis of
tumors.
RECENT ADVANCES
• Over 110 different cell types found in all 12 systems of the human body can be mapped to the 21
members of the connexin family. It is not known which human cells express Cx23, while Cx43 has
been convincingly demonstrated to be expressed in 92 different cell types, reflecting its dominance
as the most widely present human connexin, at the other end of this spectrum. [Lampe et.al ,
2022]
• E-cadherin protein degradation, which affects epithelial adhesion, is a trait of cancerous cells and is
responsible for the formation of other types of cell junctions. The normal coordinated movement of
cells in a tissue is replaced by a more individualized and disorganized movement in cancerous
tissues by these cells. [Universität ,2020]
• Genetic loss-of-function studies in vivo in physiological mouse models of cancer have revealed a causal relationship
between the loss of specific desmosome proteins and the development of certain cancers.[Dussek et al,2011]
SUMMARY
REFERENCES
• Lampe, P. D., & Laird, D. W. (2022). Recent advances in
connexin gap junction biology. Faculty reviews, 11, 14.
https://doi.org/10.12703/r/11-14
• Universität Leipzig. Less “sticky” cells become more cancerous.
Medical Xpress news. August 25, 2020.
https://medicalxpress.com/news/2020-08-sticky-cells-
cancerous.html
• Dusek, R. L., & Attardi, L. D. (2011). Desmosomes: new
perpetrators in tumour suppression. Nature reviews.
Cancer, 11(5), 317–323. https://doi.org/10.1038/nrc3051
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