CELL ADHESION MOLECULES

Dr.Vineetha Boban
Moderator:Dr.Kanchana
How
??
1.cell adhesion
molecules
2.extra cellular matrix
proteins
3.specialized cell
junctions
CELL ADHESION MOLECULES

1.Integrins
2.Selectins
3.Immunoglobulin superfamily
4.Cadherins
5.Others
(dystroglycan,mucins)
 Classification of CAM’S

Calcium Dependent CAM’s

•IgSuperfamily
•Lymphocyte Homing receptors

Calcium Independent CAM’s

•Integrins
•Cadherins
•selectins
IMMUNOGLOBULIN SUPERFAMILY

•Includes over 100 members many of which

are CAM’s
•All have one or more Ig-like domain.
•Ig-like domains are β-sheets stabilised by
di-sulphide bonding
•Intracellular adhesion molecule
(ICAM-1,ICAM-2,ICAM-3)

•Vascular Cell adhesion molecule(VCAM-1)

•Platelet endothelial Cell Adhesion

Molecule(PECAM-1)

•Neural Cell Adhesion Molecule(N-CAM)

•Mucosal Addressin(MAdCAM)
Large majority binds to components of the
extracellular matrix, but a few of them to
cells.

Common ligands are the ECM proteins :

fibronectin, vitronectin, collagen and laminin
(recognised by multiple integrins) or
members of the Ig superfam
 Intercellular Adhesion Molecule
(ICAM)

• ICAM-1 aka CD54 is a protein
encoded by the ICAM1 gene .

• This gene encodes a cell

surface glycoprotein which is typically
expressed on endothelial cells and
cells of the immune system.
 Upon cytokine stimulation, the
concentrations greatly increase.

Induced by: expressed by :

 interleukin  vascular
1 (IL-1) endothelium
 tumor  macrophages
necrosis  lymphocytes.
factor (TNF)
•ICAM-1 binds to :

•macrophage adhesion ligand-1(Mac-1) 

•leukocyte function associated antigen-1
(LFA-1)

•fibrinogen
•ICAM-1 is the primary entry receptor
for Coxsackievirus A21, an oncolytic virus.

•ICAM-1 have antagonistic effects on

the tight junctions forming the blood-
testis barrier, thus playing a major role
in spermatogenesis.
ICAM -2(CD102)

•Ligand binding site for LFA-1

•ICAM-2 is constitutively expressed on

mononuclear cells,basophils,mast cells and
platelets and expression appears to be
unaffected by cytokines.

•Present at high levels on the endothelium

and is involved in the leucocyte adherence
mechanism.
ICAM-3

•Functions as an LFA-1 ligand

•Expressed on all leucocytes and on mast
cells
•ICAM-3 cross-linking results in calcium
mobilization,tyrosine
phosphorylation,enhanced
adhesion,chemokine secretion and
modulation of basophil mediator release.
•ICAM-3 is expressed on resting leucocytes
and vascular endothelium of some tumor
vessels.

•Involved in the initiation of immune

responses and it is suggested that this
molecule may play a role in angiogenesis and
tumor development.
 Mucosal addressin(MAdCAM)

•Found in peyer’s patches and mesenteric

lymph nodes

•Binds to L-selectin to facilitate the

adherence of leucocytes to the
endothelium.
 VASCULAR ADHESION MOLECULE-
1(VCAM-1)

•Vascular cell adhesion molecule1 aka CD106

encoded by the VCAM1 gene.

•The VCAM-1 protein mediates the adhesion

of lymphocytes, monocytes, eosinophils,
and basophils to vascular endothelium.

• It also functions in leukocyte-endothelial

cell signal transduction, and it may play a
role in the development
of atherosclerosis and rheumatoid arthritis.
CYTOKINE INDUCIBLE ENDOTHELIAL
CAM
•Expressed on macrophage,dendritic cell,bone
marrow stem cells and respiratory epithelium
cell line.

•Expression On umbilical vein endothelial cells

induced by IL-1,TNF-α or LPS.

•Expression on endothelial cells induced by

IL-4,IL-13.
PLATELET ENDOTHELIAL CELL ADHESION
MOLECULE[CD31]

•PECAM-1 is a CAM expressed on endothelial

cells and circulating
platelets,monocytes,neutrophils.
•Angiosarcomas
•Hemangioendotheliomas
•Plays an important role in mediating
•Hemangiomas
neutrophil and monocyte
•Kaposi’s transendothelial
sarcoma
migration.
 NEURAL- CELL ADHESION
MOLECULE(N-CAM)[CD56]

•Adrenal cortex &

medullaSmall blue
Renalsurfaces
•Present on •the proximal tubules
of nerve and glial
cells
round
•Follicular cell
epithelium of
tumors with
thyroid
•Gastric parietal cells
CD99 cascades that
•Activates second-messenger
•Cardiac muscle
promote nerve growth.islet cells
•Pancreating
•Peripheral nerve
 INTEGRINS
Involved in cell-extracellular matrix
adhesion and cell-cell adhesion.
• Structure: heterodimer consisting of two
transmembrane glycoprotein subunits
(α and β), which are non-covalently bound.
• Functional integrins always have: one α
subunit and one β subunit.
• Both subunits contribute to ligand
binding.
• About 18 α subunits and 8 β subunits
have been identified, giving ~24 unique
integrins
Integrin binds directly to collagen
•α1β1
•α2β1
Integrin binds indirectly to collagen
•First binds to fibronectin
•α5β1
Integrin fix epithelial cells to the basement
membrane
•The basement membrane is formed of two layer
of connective tissue separated by space.
•The endothelial cells sit on the basal lamina of
the basement membrane.
•Anchoring integrin: α3β1-α6β1-α7β1
Integrin ligands:
•ECM proteins-fibronectin,collagen,laminin
•Ig superfamily members
(VCAM-1,MAdCAM-1)
•Coagulation factors
•Fibrinolytic factors
•Complement factos C3b
Very Late Antigen-4 [VLA-4]

•α4β1
•Found on the surface of the monocytes
•In the inflammatory states,VLA-4 binds to
VCAM-1
Lymphocyte function associated antigen-
1[LFA_1]
•αLβ2,CD11a/CD18
•Found on the surface of all leucocytes and
mainly on the monocyte.
•In the inflammatory states,the endothelial
cells starts to express the ICAM-1 on its
surface to bind to LFA-1 of the monocytes
and to differentiate to macrophage in the
interstitial space.
Mac-1(CD11b/CD18) αMβ2

•Abundant in cells of the myeloid lineage

•Also present in monocytes

P150/95(CD11c/CD18) αxβ2

•Present in myeloid cells and monocytes

•Highly expressed by tissue macrophages.
Cytoadhesins

•β3 subunit
•Consists of platelet glycoprotein IIb/IIIa
Complex (CD41/Cd61)and the vitronectin
receptor.
•Gp IIb/IIIa is primarily found on
megakaryocytes and platelets.
•Vitronectin receptor (CD51/CD61) appears
on most mesenchymal cells.
Key integrin function: cell migration

The clustering of integrins - formation of

focal adhesions.

•Signals generated at focal adhesions help to

regulate cell division, growth and survival, as
well as being important for cell migration.
•Integrins are key molecules during early
development, fertilization, gastrulation,
implantation, placentation, nervous system
formation, myogenesis and blood vessel
formation.
•Integrins also regulate extracellular matrix
(ECM) assembly →proper interactions of
cells with ECM is critical for correct
development.
 SELECTINS

•All selectins are single-chain

transmembrane glycoproteins.

•Family of CAM’s which bind to specific

sugar determinants on the surface of
adjacent cells.

•The selectins are physiologically important

in inflammation, lymphocyte homing,
immunological responses, and homing of bone
marrow stem cells.
•They are involved in trafficking of cells of
the innate immune system, T lymphocytes
and platelets.

•An absence of selectins or selectin ligands

has serious consequences , leading to
recurrent bacterial infections and
persistent disease.

•They play a role in atherosclerosis,

ischemia-reperfusion injury, inflammatory
diseases, and metastatic spreading of some
cancers.
•Composed of :

•Lectin domain

•Epithelial growth factor(EGF)-like

region

•Complement regulatory like modules

•Leucocyte expressed L-Selectin[CD62L]

•Endothelial expressed E-selectin[CD62E]

•P-selectin expressed by both platelets and

endothelial cells.[CD62P]
 P-Selectin(CD62)
•Found on the endothelial cells to help the
recruitment of neutrophils
•Functions as a vascular ligand for most
myeloid and lymphoid cells.
•Stored in intra-cellular granules(Weibel-
Palade bodies and in α-granules of
platelets) and can be rapidly translocated
to the cell-surface when endothelial cells
are stimulated with agents such as
C5a,histamine,thrombin,phorbol esters or
leukotriene C4.
Leukocyte interaction with endothelial P-
selectin has been shown to alter leucocyte
cellular functions including
• Superoxide production
• integrin-mediated phagocytosis
• production of cytokines and chemokines.
 E-Selectin

•E-Selectin is not expressed on the surface

of unstimulated endothelium but is induced
within several hours following exposure to
either IL-1,TNF-α or bacterial endotoxins.

•Surface expression of E-Selectin in vitro

is relatively transient ,with endothelial
expression levels peaking at 4-6hours and
approaching baseline levels by 24hrs.
P- and E-selectins bind to common sites:

•carbohydrates,including sialylated Lewis x

related structures

•Sulfated polysaccharides
(heparin,fucoldan)

•phosphated monosaccharides and

polysaccahrides
 L-Selectin

•Was originally identified as a peripheral

lymph node homing receptor responsible for
lymphocyte adhesion to high endothelial
venules in lymph node.

•Expressed on the tips of the microvilli of

most
leucocytes,neutrophils,eosinophils,monocytes,
naïve T and B cells as well as on the surface
of some activated T-cells and memory cells.
•L- Selectin mediates leucocyte margination
and tethering to endothelium under conditions
of shear stress associated with blood flow.

•L-Selectin is irreversibly and rapidly shed

from the leucocyte cell surface by
endogenous membrane bound proteases.
 Cadherins

•important in the formation of adherens

junctions to bind cells with each other.

•Dependent on calcium (Ca2+) .

•Cell-cell adhesion is mediated by

extracellular cadherin domains, whereas
the intracellular cytoplasmic tail associates
with numerous adaptor and signaling
proteins, collectively referred to as the
cadherin adhesome
•Classic cadherins

•Desmosomal cadherins

•Proto-cadherins
Type -1 Classic Cadherins
The cytoplasmic terminal end binds to two
proteins:
•P120 catenin
•β-catenin + α-catenin
•α-catenin anchor the cadherin to the
cytoskeleton actin filaments.
 N-Cadherin

Found in the neurons,muscle tissue

 E-cadherin

Found in the epithelial cells

E-cadherin-Catenin complex functions as a
master molecule in regulating not only cell
adhesion but also
polarity,differentiation,migration,proliferati
on and survival of epithelial cells.
 P-Cadherin

Found in the placenta,epidermis

 Desmosomal cadherin

•Desmocolin(1,2,3)
•Desmoglein(1,2,3,4)
Cytoplasmic terminal ends bind to 2
proteins:
•Plakoglobin-γ catenin
•Plakophilin
These two proteins will bind to
desmoplakin-intermediate
filament(keratin)
 genetic defects:
Mutations: •SAM syndrome,
The integrity of the epidermis
• palmoplantar • an depends on the
keratoderma 
cohesion between keratinocytes,
inflammatory
•forms
and desmosomes are the main
typeadhesion
of peeling
of epidermolysi
structures skindisease
s bullosa •Netherton
syndrome
 OTHER CAM’S

•Proteoglycans-mediates lymphocyte
binding to mucosal high endothelial
venules.
•Platelet GpIb-IX complex,contains a
thrombin binding site and a vWF binding
site which is responsible for initial binding
of the platelet to the rest of the
sub-endothelium.
CELL
ADHESION
MOLECULES IN
VARIOUS
DISEASES.
 Cytoadhesion molecules play an important
role in the pathophysiology of
cardiovascular, neoplastic, infectious and
skin diseases.
Heart septation defects
ventricular and atrial septal defects, and
persistent truncus arteriosus,associated with
defects of migration of the cardiac neural
crest cells are among the most highly
occurring human congenital heart defects.
DiGeorge syndrome
characterized by heart defects,
craniofacial abnormalities and severe
retardation, has been linked to chromosome
deletions that result in migratory defects of
the neural crest cells
 Hirschsprung's disease
• characterized by impaired bowel
movement, is related to defects in
migration of the vagal and sacral neural
crest lineages.

Waardenburg's syndrome
•characterized by abnormal
pigmentation, results from the impaired
migration of neural crest cells that give
rise to the melanocytes of the skin
•Other human syndromes, including Alagille,
Carpenter, CHARGE, Ivemark, and
Leopard/Noonan syndromes, result in
abnormalities that suggest impairments of
the neural crest migration, with known or
unknown molecular reasons
atherosclerosis
 References

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