Cell Junctions and Cell Adhesion by xiuliliaofz


									                                           Review of Literature

            Cell Junctions and Cell Adhesion

       The bulding technologies of animals and plants are
different, and each type of organism is formed of many types
of tissues, in which the cells are assembled and bound together
in different ways. In both animals and plants, however, an
essential part is played in most tissues by the extracellular
matrix. This complex network of secreted extracellular
macromolecules has many functions, but first and foremost it
forms a supporting framework.
It helps hold cells and tissues together, and, in animals, it
provides an organized environoment within which migratory
cells can move and interact with one another in orderly ways.
The extracellular matrix, however, is only half the story. In
animals especially, the cells of most tissues are bound directly
to one another by cell-cell junctions. These too are of many
types, serving many purposes in addition to mechanical
attachment; but without them, human bodies would disintegrate
(Alberts et al., 2002).
       In vertebrates, the major tissue types are nerve, muscle,
blood, lymphoid, epithelial, and connective tissues. Connective
tissue and epithelial tissue represent two extremes of
organization. In connective tissue, the extracellular matrix is
plentiful, and cells are sparsely distributed within it. The matrix
is rich in fibrous polymers, especially collagen, and it is the
matrix – rather than the cells – that bears most of the
mechanical stress to which the tissue is subjected. Direct
attachments between one cell and another are relatively rare.
       In epithelial tissue, by contrast, cells are tightly bound
together into sheets called epithelia. The extracellular matrix is
scanty, consisting mainly of a thin mat called the basal lamina,

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which underlies the epithelium. The cells are attached to each
other by cell-cell adhesions, which bear most of the mechanical
stresses (Alberts et al., 2002).
Cell junctions
         Specialized cell junctions occur at points of cell-cell and
cell-matrix contact in all tissues, and they are particularly
plentiful in epithelia. The interacting plasma membranes (and
often the underlying cytoplasm and the intervening
intercellular space as well) are highly specialized in these
regions (Alberts et al., 2002).
Cell junctions can be classified into three functional
 I.      Occluding junctions seal cells togethet in an epithelium
         in a way that prevents even small molecules from
         leaking from one side of the sheet to the other.
 II. Anchoring junctions mechanically attach cells (and their
         cytoskeletons) to their neighbors or to the extracellular
 III. Communicating junctions mediate the passage of
         chemical or electrical signals from one interacting cell to
         its partner.
The major kinds of intercellular junctions within each group
are listed in Table (3).
 Occluding junctions from a selective permeability
 barrier across epithelial cell sheets
         Tight junctions are occluding junctions that are crucial in
 maintaining the concentration differences of small hydrophilic
molecules across epithelial cell sheets.
  Anchoring junctions connect the cytoskeleton of a
    cell either to the cytoskeleton of its neighbors or to the
    extracellular matrix

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       The lipid bilayer is flimsy and cannot by itself transmit
large forces from cell to cell or from cell to extracellular
matrix. Anchoring junctions solve the problem by forming a
strong membrane-spanning structure that is tethered inside the
cell to the tension-bearing filaments of the cytoskeleton. (Fig 4)

Table (3): A Functional Classification of Cell Junctions


1- tight junctions (vertebrates only)
2- septate junctions (invertebrates mainly)


   Actin filament attachment sites
1- cell-cell junctions (adherens junctions)
2- cell-matrix junctions (focal adhesions)
   Intermediate filament attachment sites
1- cell-cell junctions (desmosomes)
2- cell-matrix junctions (hemidesmosomes)


1- gap junctions
2- chemical synapses
3- plasmodesmata (plants only)

   (Alberts et al., 2002)

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Figure (4): Anchoring junctions in an epithelial tissue.
This drawing illustrates, in a very general way, how anchoring junctions
join cytoskeletal filaments from cell to cell and from cells to extracellular
matrix (Alberts et al., 2002).
       Anchoring junctions are widely distributed in animal
tissues and most abundant in tissue that are subjected to severe
mechanical stress, such as heart, muscle, and epidermis.
They are composed of two main clases of proteins (Fig.5).
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 interacellular matrix
or the extracellular domains of specific transmembrane
adhesion proteins on another cell. In addition to anchor

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proteins and adhesion proteins, many anchoring junctions
contain intracellular signaling proteins that enable the junctions
to signal to the cell interior (Alberts et al., 2002).

Figure (5): The Construction of an anchoring junction from two
classes of proteins. This drawing shows how intracellular anchor proteins
and transmembrane adhesion proteins from anchoring junctions (Alberts
et al., 2002).
Anchoring junctions occur in two functionally different
 I-  Adherens junctions and desmosomes hold cells together
     and are formed by transmembrane adhesion proteins that
     belong to the cadherin family.
 II- Focal adhesions and hemidesmosomes bind cells to the
     extracellular matrix and formed by transmembrane
     adhesion proteins of the integrin family.

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       On the intracellular side of the membrane, adherens
junctions and focal adhesions serve as connection sites for
actin filaments, while desmosomes and hemidesmosomes serve
as connection sites for intermediate filaments (table 3,4 and
Figure 6-8) (Alberts et al., 2002).
 Gap junctions are communicating composed of
 clusters of connexons that allow molecules smaller than
 about 1000 daltons to pass directly from the inside of
 one cell to the inside of the next.
       Gap junctions are important in coordinating the activities
    of electrically active cells, and they have a coordinating role
    in other groups of cells as well (Alberts et al., 2002).
Table (4): Anchoring junctions

                 ADHESION PROTEIN     LIGAND                CYTOSKELETAL          ANCHOR
                                                             ATTACHMENT           PROTEINS

Adherens junction Cadherin           Cadherin in           actin filaments     α-and β-catenins,
                  (E-cadherin)       neighboring cell                             Vincculin,
                                                                                α- actin,

Desmosome          Cadherin         desmogleins and          intermediate       desmoplakins,
                  (desmoglein ,     desmocollins in        filament            plakoglobin
                   desmocollin)     neighboring cell                           (γ-catenin)

Focal adhesion      integrin        extracellular matrix     actin filament     talin, vinculin,
                                     Proteins                                  α- actin,filament

Hemidesmosome       integrinα6β4,   extracellular matrix        intermediate     plectin,
                    BP 180           proteins                   filament         BP230

(Alberts et al., 2002)

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Figure (6): Desmosomes. (A) An electron micrograph of three
desmosomes between two epithelial cells in the intestine of a rat. (B) An
electron micrograph of a single desmosome between two epidermal cells
in a developing newt, showing clearly the attachment of intermediate
filaments. (C) The structural components of a desmosome. On the
cytoplasmic surface of each interacting plasma membrane is a dense
plaque composed of a mixture of intracellular anchor proteins. A bundle
of Keratin intermediate filaments is attached to the surface of each
plaque. Transmembrane adhesion proteins of the cadherin family bind to
the plaques and interact through their extracellular domains to hold the
adjacent membranes together by a Ca2+-dependent mechanism (Alberts et

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Figure (7): Adherens junctions. Adherens junctions, in the form of
adhesion belts, between epithelial cells in the small intestine. The beltlike
junction encircles each of the interacting cells. Its most obivious feature is

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a contractile bundle of actin filaments running along the cytoplasmic
surface of the junctional plasma membrane (Alberts et al., 2002).

 Figure (8): A summary of the junctional and nonjunctional adhesive
mechanisms used by animal cells in binding to one another and to the
extracellular matrix.
 The junctional mechanisms are shown in epithelial cells, while the
nonjunctional mechanisms are shown in nonepithelial cells. A junctional
interaction is operationally defined as one that can be seen as a
specialized region of contact by conventional and/or freeze-fracture
electron microscopy. Note that the integrins and cadherins are involved in
both nonjunctional and junctional cell-cell (cadherins) and cell-matrix

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(integrins) contacts. The cadherins generally mediate homophilic
interactions, whereas the integrins mediate heterophilic interactions (Both
the cadherins and integrins act as transmembrane linkers and depend on
extracellular divalent cations to function; for this reason, most cell-cell
and cell-matrix contacts are divalent-cation-dependent. The selectins and
integrins can also act as heterophilic cell-cell adhesion molecules: the
selectins bind to carbohydrate , while the cell-binding integrins bind to
members of the immunoglobulin superfamily. The integrins and integral
membrane proteoglycans that mediate nonjunctional adhesion to the
extracellular matrix are discussed later. (Alberts et al., 2002).

Cell-cell adhesion
       To form an anchoring junction, cells must first adhere.
Cells adhere to each other and to the extracellular matrix
through cell-surface proteins called cell adhesion molecules
(CAMs) – a category that includes the transmembrane adhesion
proteins. CAMs can be cell-cell adhesion molecules or cell-
matrix adhesion molecules. Some CAMs are Ca2+ dependent,
whereas others are Ca2+ independent. The Ca2+ dependent
CAMs seem to be primarily responsible for the tissue-specific
cell-cell adhesion seen in early vertebrate embryos, explaining
why these cells can be disaggregated eith Ca 2+ chelating agents
(Table (5) and figure (9)) (Alberts et al., 2002).
       CAMs were initially identified by making antibodies
against cell-surface molecules and then testing the antibodies
for their ability to inhibit cell-cell adhesion in a test tube.
Those rare antibodies that inhibit the adhesion were then used
to characterize and isolate the adhesion molecule recognized by
the antibodies (Alberts et al., 2002).

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Table (5): Cell Adhesion Molecule Families
              SOME FAMILY  Ca2+OR Mg2+ HOMOPHILIC OR CYTOSKELETON                      CELL JUNCTION

Cell-cell Adhesion
Classical Cadherin E,N,P,VE         Yes     homophilic          actin filaments (via      adherens
                                                                      Catenins)            Junctions

Desmosomal          desmoglein      Yes      homophilic         intermediate filaments desmosomes
Cadherin                                                         (via desmoplakin,
                                                                   Plakoglobin, and
                                                                   Other proteins)

Ig family members     N-CAM         No        both                  unknown                 No

Selectin (blood cells L,E, and      Yes       Heterophilic          actin filaments         No
and endothelial       P-selectin
cells only)

Integrins           αl β2 (LFA-1)    Yes    Heterophilic           actin filaments          No
on blood cells

Cell-Matrix Adhesion
Integrins      many types           Yes    heterophilic actin filaments (via focal adhesion
                                                             talin, filamin,
                                                           α-actin, and vinculin)

                    α6 β4           Yes    Heterophilic          intermediate     hemidesmosomes
                                                             filament (via plectin)

Traansmembrane syndecans            no     heterophilic        actin filament              no

(Alberts et al., 2002).

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Figure (9): Three mechanisms by which cell-surface molecules can
mediate cell-cell adhesion. Although all of these mechanisms can

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operate in animals, the one that depends on an extracellular linker
molecule seems to be least common (Alberts et al., 2002).

Cells Contact Each Other Via Adhesion Molecules
       Cell adhesion is a mechanical necessity for multicellular
organisms. Large groups of adherent cells sharing a common
organ-specific function are termed tissues. The behavior of
cells and tissues depends on information transfer from
surrounding molecules-either those fixed to the surfaces of
contiguous cells, or those diffusible within the proteinaceous
extracellular matrix separating the cells of adherent tissues
(Epstein, 2003).
       Adhesion to a substratum is a prerequisite for replication
of many cell types, a growth requirement termed anchorage
dependence. Conversely, many cell types will stop
proliferating once a certain level of intercellular contact
(confluence or crowding) has been reached: this process is
termed density-dependent growth arrest or contact inhibition.
Both anchorage dependence and contact inhibition are
mediated by plasma membrane cell adhesion molecules
(CAMs). Dysfunction of adhesion proteins may thus disrupt
cell growth control, and contribute to cell transformation
(Epstein, 2003).
       Cell adhesion molecules participate in homophilic or
heterophilic binding interactions. Homophilic binding occurs
when the extracellular domain of one CAM binds to a similar
domain of the same CAM expressed by another cell, whereas
heterophilic binding denotes interaction between different
CAM families. Adhesionreactions between cells of the same
type are termed homotypic, whereas heterotypic adhesion

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occurs between diferent lineages. Adhesive interactions that
cause cell clumping are termed aggregation reactions. Hence,
platelets may either adhere (e.g., to endothelium) or aggregate
(to each other); in Vitro assays distinguish defective platelet
fall into four major families (fig.10)
 i.    Cadherins – calcium-dependent CAMs which link
       homotypic adhesion to cell proliferation (via
       intermediary molecules termed catenins).
 ii. Selectins (LEC-CAMs) – mediators of initial (weak)
       heterotypic adhesion events between leukocytes,
       platelets, and activated endothelial cells.
 iii. Integrins – heterodimeric CAMs which link heterophilic
       cell adhesion with the extracellular matrix and
       intracellular signaling.
 iv. Immunoglobulin-like domain CAMs-mediators of both
       homophilic cell adhesion (Epstein, 2003).

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Figure (10): Major families of cell-adhesion molecules (CAMs).
Integral membrane proteins are built of multiple domains. Cadherin and
the immunoglobulin (Ig) superfamily of CAMs mediate homophilic cell-
cell adhesion. For cadherin, calcium binding to sites between the five
domains in the extracellular segment is necessary for cell adhesion; the N-
terminal domain causes cadherin to dimerize and to bind cadherin dimers
from the opposite membrane. The Ig superfamily contains multiple
domains similar in structure to immunoglobulins. In a heterophilic
interaction, the lectin domain of selectins binds carbohydrate chains in
mucin-like CAMs on adjacent cells in the presence of Ca2+.. The major
cell-matrix adhesion molecule, integrin, is a heterodimer of α and β
subunits (Lodish et al., 2000).

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       Adhesion molecules do more than just stick together.
CAMs act as both effectors and sensors of intracellular
signaling, enabling adhesive interactions to be modified in
response to phosphorylation events within the cell. The variety
of adhesion molecules reflects functional differences between
these superfamilies in terms of adhesive strength, tissue
specificity, and speed of cell binding. In general, the strength
of cell adhesion depends more on the number of adhesion
molecules than on the affinity of CAM binding (usually weak).
The main clinical pathologies involving cell adhesion
molecules are: thrombosis, inflammation, and cancer
metastasis (Epstein, 2003).
Adhesion Proteins and Receptors
       Adhesion receptors and their ligands mediate cell-to-
matrix and cell-to-cell interaction and include the selsctins, the
integrins, the immunoglobulin family, and miscellaneous
others (Quesenberry and Colvin, 2001). Hematopoietic stem-
progenitor cells (mostly expressing the CD34 antigen) have
multiple adhesion receptors, allowing them to attach to cellular
and matrix components within the marrow sinusoidal spaces,
thereby facilitating their homing and lodgement in the marrow,
and providing the close cell-cell contacts required for cell
survival and regulated steady-state proliferation. Adhesive
receptors and their ligands, present on hematopoietic stem-
progenitor cells, and components of the hematopoietic
microenvironment. Six subgroups of receptors, the integrins,
immunoglobulins, lectins (selectins), sialomucins, hyaladherin
(CD44, H-CAM), and other receptors such as CD38 (ADP-

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ribosyl cyclase), CD144 (cadherin), and CD157 (BST-1), are
shown listing mostly interactions involving CD34-positive
cells and progenitors. Thus receptor-ligand interactions that
regulate the trafficking of mature leukocytes are not included
exhaustively (Abboud and Lichtman, 2001).
Cell-Cell Adhesion and Human Cancers
       Cell-cell adhesion participates in histogenesis and plays
a critical role in the establishment and maintenance of cell
polarity and cell society. It was known as early as the 1940s
that the mutual adhesiveness of cancer cells is significantly
weaker than that of the corresponding normal cells.
       Reduced cell-cell adhesiveness allows cancer cells to
disobey the social order, resulting in destruction of the
histological structure, the morphological hallmark of malignant
tumors. In cancers in vivo, particularly the diffuse type, tumor
cells are dissociated throughout the entire tumor masses, lose
their cell polarity, and infiltrate the stroma in a scattered
manner. One of the most characteristic features of cultured
cancer cells in vitro is loss of "contact inhibition" which
reflects disordered signal transduction from cell-cell adhesion
to cell growth. Moreover, invasion and metastasis, which are
the most life-threatening properties of malignant tumors, are
considered to be later, but critically important, carcinogenetic
steps. The invasion and metastatic processes themselves consist
of sequential steps involving host-tumor interactions. In order
for a metastatic nodule to form, cancer cells must leave the
primary cancer nests, invade the surrounding host tissue, enter
the circulation, lodge in a distant vascular bed, extravasate into
the target organ, and proliferate. The dissociation of cancer
cells form cancer nests is a crucial step and the suppression of
cell-cell adhesiveness may trigger the release of cancer cells

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from the primary cancer nests and confer invasive properties
on a tumor. Indeed, the tumor cells of solid tumors with high
metastatic potentials are often focally dissociated at the
invading fronts. Therefore, reduced cell-cell adhesiveness is
considered indispensable for both early and late carcinogenetic
steps. Human cancers appear to prossess both irreversible and
reversible mechanisms for inactivating the cell-cell adhesion
system (Hirohashi, 1998).

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 1. The Integrin Family
       The integrins are a family of heterodimeric membrane
glycoproteins express on diverse cell types, which function as:
1- The major receptors for extracellular matrix.
2- Cell-cell adhesion molecules.
As adhesion molecule they play an important role in numerous
biological processes such as platelet aggregation,
inflammation, immune function, wound healing, tumor
metastasis and tissue migration during embryognesis. There is
now increasing evidence to implicate integrins in signaling
pathways, transmitting signals both into and out from cells.
       All integrins consist of two non-covalently associated
subunits, () and (). The integrins were originally classified
into three subfamilies (1 integrins or VLA proteins; 2
integrins or leucans and β3 integrins or cytoadhesins), in which
a common  subunit was thought to associate with a number of
different () subunits.
       However, two classifications are now less rigid since to
date at least 12 different () subunits and 8β subunits have
been identified.
       Furthermore, individual () subunits have been shown to
associate with more than one type of  subunit (Abboud and
Lichtman, 2001).
 2. Immunoglobulin Superfamily
       Since the concept of the immunoglobulin superfamily
(Igsf) was proposed in 1982 (Williams, 1982), it has expanded

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to embrace over 70 members, including both single and multi
gene representatives. The roles of the members are
multifarious, but are linked by the common theme of
controlling cell behavior. Molecules acting as signal transuding
receptors (for example the PDGF and IL1 receptors exert such
control). Or as intercellular adhesion molecules. As would be
expected of such molecules, with the exception of single family
member found intracellulary (the skeletal muscle C-protein)
and three members which probably exist only as secreted
proteins (the serum protein 1B-gp, the link protein of basement
membranes and proteoglycen, perlecan), they can all be found
as cell surface molecules.
   The immunoglobulin superfamily designates a group of
containing one or more amino acid repeats also found in
immunoglobulins and consists of PECAM-1 (CD31), ICAM-
3/R (CD50) and ICAM-1 (CD54), LFA-3 (CD58), ICAM-2
(CD 102), VCAM-1 (CD106), KIT (CD117), and PRR2, a
molecule related to CD155, which serves as a poliovirus
receptor. VCAM-1 is upregulated by inflammatory cytokines
Immunoglobulin-like adhesion molecule also include NCAM,
a neural adhesion molecule that binds lymphocytes but not
hematopoietic progenitors; Thy-1, a stem cell antigen MHC
classes I and II; and CD2, CD4, and CD8 (Figure) (Abboud
and Lichtman, 2001).
 3. The Lectins (Selectins) Family
       Homing of stem cells requires lectin receptors with
galactosyl and mannosyl specificities. The selectins are a
family of adhesion molecules. Each containing type C lectin
structures. The leukocyte selectin (L-selectin, CD62L) is
expressed on hematopoietic stem-progenitors and mediates

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adhesive interactions with other receptors (addressins), such as
the CD34 sialomucin present on specialized endothelium, using
sialylated fucosyl-glucoconjugates. The CD34 receptor on stem
cells, however, does not bind L-selectin, as a putative L-
selectin ligand yet to be defined exists on these cells. The
selectin family also contains CD62E, which is an E-selectin
constitutively expressed on marrow sinusoidal endothelium,
and regulates the transmigration of leukocytes as well as
CD34-positive stem cell homing. The third member of this
family is P-selectin, which is found on platelets and is able to
bind hematopoietic stem cells, using a mucin receptor, the P-
selectin glycoprotein ligand (PSGL-1), which binds to all three
selectins. These proteins are responsible for leukocyte rolling
over endothelium to form, and mediating cellular homing
events using specialized hight endothelial venule lymphocyte
homing sites (Abboud and Lichtman, 2001).

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