1. Cell adhesion
molecules and
matrix proteins
Presented by :
Navneet Kaur
M.Pharm (P’cology)
2nd Sem

2. EXTRACELLULAR MATRIX
Three groups of macromolecules,
which are often physically
associate, constitute the ECM:
1. fibrous structural proteins such as
collagens and elastins
2. a diverse group of adhesive
glycoproteins
3. proteoglycans and hyaluronic
acid
These macromolecules are present
in intercellular junctions and cell
surfaces and may assemble into 2
general organizations: interstitial
matrix and basement
membrane(BM)

4. Collagen : provide extracellular framework for
all multicellular organisms
 Composed of a triple helix of 3 polypeptide α chains
having a gly-x-y repeating sequence. Currently 27
different types of collagens encoded by 41 genes
dispersed on at least 14 chromosomes are known.
-Type I, Type II, Type III,Type V,Type XI: interstitial or
fibrillar collagens.
- Type IV: nonfibrillar and main component of BM together
with laminin
Fibrillar collagen is synthesised from procollagen, a
precursor molecule derived from preprocollagen,which is
transcribed from collagen genes.

5. Elastin,fibrillin,and elastic fibres:
Tissues such as blood vessels,skin,uterus,lungs
require elasticity for their function.
-Ability of tissues to recoil is provided by elastic
fibres.These fibres can stretch to several times their
length and then return to their original size after
release of tension. Elastin fibres consist of a central
core made of elastin, surrounded by a peripheral
network of microfibrils.The peripheral microfibrillar
network that surrounds the core consists largely of
fibrillin ,a 350 kD secreted glycoprotein which
associates either with itself or with other components
of ECM.

6. Cell adhesion proteins: It basically
include fibronectin and laminin.
Fibronectin is a large
protein that binds to
many molecules,such
as
collagen,fibrin, proteogl
ycans and cell surface
receptors.
Laminin is the most
abundant glycoprotein
in the basement
membrane and has
binding domains for
both ECM and cell
surface receptors.

7. Proteoglycans and hyaluronic
acid(HA): Proteoglycans consists of a core protein linked to one
or more polysaccharides called as glycosaminoglycans
(GAGs). Some of the most common are heparan
sulfate, chondroitin sulfate and dermatan sulfate. They
have diverse role in regulating connective tissue
structure and permeability. By binding to other proteins
and fibroblast growth, they act as modulators of cell
growth and differentiation.
 HA is a polysaccharide of GAG family found in ECM of
many tissues. It binds a large amount of water forming a
viscous hydrated gel that gives connective tissue the
ability to resist compression forces. It also provides
lubrication to many type of connective tissue,notably for
the cartilage in joints.

8. CELL ADHESION MOLECULES are
proteins located on cell surface involved
with the binding with other cells or ECM in
process called cell adhesion.
Cell
adhesion
molecules
CAMs
cadherin
s
integrins
selectins

9. IgSF CAMs: Immunoglobin superfamily
CAMs are either homophilic or heterophilic and
bind integrins or different IgSF CAMs. Some
molecules of this family are:
-NCAMs (neural CAMs)
-ICAM(intercellular CAMs)
-VCAMs(vascular CAMs)
-PECAMs(platelet-endothelial CAMs)
CADHERINS:Cadherins are Ca++Dependent
cell-cell adhesion molecules. They are rapidly
degraded by proteases in the absence of Ca++.
There are 3 major types: E-
cadherins(epithethial),P -cadherins(placental),
N-cadherins(neural)
.

10. Cadherins can have homophilic binding or
heterophilic binding.

12. INTEGRINS: are receptors that mediate
attachment between a cell and the tissues surrounding
it,which may be other cells or the ECM. Integrins shows
heterophilic binding
 Integrins are a family of
transmembrane
glycoproteins that are
composed of 2 chains, α
and β.There are 40 different
types of α chains and 8
types of β chains that can
combine to form a large
number of different integrin
molecules. The α chain has
binding sites for Ca++ and
Mg++ which are needed for
integrins to adhere. The
cytoplasmic tail of integrins
is connected to a linker
protein that connects to the

13. Integrins pass information about the chemical
composition and mechanical status of ECM into
cell
Involved in cell signaling and regulation of cell
cycle,shape and motility .
Intracellular domains interact with variety of
signaling and structural proteins:
 Talin and vinculin (adapter proteins) to form
focal
adhesions
 Link to actin to form stress fibers
 Paxillin (adapter proteins) to activate FAK (focal
adhesion kinase)

14. Functions of integrins:
1. Attachment of cell to ECM
2. Signal transduction from ECM to cell
have relation to-
-cell growth
-cell division
-cell survival
-cellular differentiation
-apoptosis
-cell migration during embryogenesis ,
thrombosis, haemostasis,wound
healing etc.

15. SELECTINS: are single chain transmembrane
glycoproteins,they have lectin like carbohydrate
binding domain.
• endothelial
• Transfer leukocytes to
particular tissues
E-selectin
• leukocytes
• Responsible for
inflammatory reaction
L-selectin
• platelet
• In blood clotting and
platelet activation
P-selectin

17.  The best characterised ligand for three selectins
is P-selectin glycoprotein ligand-1 (PSGL-
1), which is a , mucin type glycoprotein
expressed on all WBCs. The name selectin
comes from the words “selected” and “lectins”
which are a type of carbohydrate recognizing
proteins.
 Another ligand for E-selectin is sialylated Lewis X
Ag (sLe(x)).

18. PHYSIOLOGICAL
ROLES:
•Leukocyte-endothelial
interactions:
The following steps are
included :
1. leukocyte trapping or
rolling
2. leukocyte activation
and adhesion
3. diapedesis
4. Termination

19.  Blood coagulation: vascular injury
produces endothelial denudation or
retraction, platelets rapidly adhere to exposed
sub endothelium. The platelet adherent to
damaged vessel wall may directly recruit
leukocytes by initiating selectin- integrin
dependent leukocyte adhesion to surface
bound platelets. Moreover accumulated
leukocytes bound to adherent platelets may
promote fibrin deposition, thereby contributing
to thrombus formation.

20. Morphho genesis and CAMs:
The ability of cells to detach from a formerly
cohesive structure and to migrate and contribute
to formation of new tissues is a key event during
morphogenesis.
- early development
- implantation of embryo into uterine epithelium
involves both E- and P- cadherin.
-Gastrulation and embryogenesis

21. THERAPEUTIC UTILITY:
1. cancer: selectins can be used as
nanodevices to treat cancer. Researchers are
trying to create a device capable of killing
cancer cells circulating in the blood.
2. osteoporosis: osteoporosis is a disease
that occurs when bone creating cells called
osteoblasts become to scarce. Osteoblast
developed from stem cells can be able to
treat osteoporosis by adding stem cells to a
patient’s bone marrow. E-selectins are
constitutively expressed in the bone
marrow, and researchers have shown that
tagging stem cells with a certain glycoprotein
causes those cells to migrate to bone marrow.

22. 3.Ischemic heart disease: GPIIb/IIIa
antagonists (like
abciximab,tirofiban,eptifibatide)are effective
antithrombotic agents. As compared to alone
thrombolytic agent, combination of GPIIb/IIIa
antagonists and a thrombolytic agent produces
more rapid and extensive clot lysis,reduces
the risk of re-occlusion and dimnishes infarct
size.
Trials of these antagonists along with other
thrombolytic agents and anticoagulants are
currently ongoing in MI and unstable angina.
Other conditions which can be benefited are
stroke, thrombotic thrombocytopenic purpura

23. 4.Inflammatory diseases: Overzealous
accumulation of leukocytes in tissues contributes
to a wide variety of diseases.
 Atherosclerosis
 Asthma and COPD
 Chronic IBD
 Rheumatoid arthritis
 Multiple sclerosis
 Juvenile diabetes etc
therapeutic strategies are thus directed to reduce
or prevent leukocyte-endothelial cell interactions
and communication, in order to limit the
progression of inflammatory diseases.

24. 5.Bacterial diseases: advantage of
adherent state to bacterias:
 required for colonization and for subsequent
development of disease
 provides significantly greater resistance
against clearance by normal cleansing
mechanisms,killing by normal immune
factors,bacteriolytic enzymes and antibodies
 better ability to acquire nutrients,further
enhancing ability to survive and infect the
host.
Thus the target is to reduce contact between
host tissues and pathogens,either by
prevention or reversal of adhesion(anti-
adhesive agents) of infectious agents.

25. Glycoprotein IIb/IIIa antagonists
Main adhesion molecule involved in platelet
aggregation is the membrane protein, GPIIb/IIIa
complex. GPIIb/IIIa is an integrin receptor present
at high density on platelets. It exists as an inactive
form in resting platelets. Platelet
activation, associated with the release of agonists
(epinephrine, serotonin, thromboxane A2) from the
platelet-dense granules, leads to the recruitment of
the internal pool of glycoprotein IIb/IIIa
receptors, and this increases the number of surface
receptors by 50%. It induces conformational
changes of GPIIb/IIIa, which becomes competent
to bind soluble plasma fibrinogen. The receptor-
bound fibrinogen acts as a bridge between two
GPIIb/IIIa molecules on adjacent platelets. This is
the final common pathway of platelet aggregation.

27. MOA: GP IIb/IIIa is unable to bind fibrinogen
unless the platelet is first activated by an
agonist, which then induces a conformational
change in GP IIb/IIIa receptor, exposing the
binding domain and
rendering the molecule a competent fibrinogen
binder. GP IIb/IIIa antagonists block the final
step in platelet aggregation triggered by all
platelet activators.
INTRAVENOUS ANTAGONISTS:
Abiciximab, Eptifibatide, Tirofiban and
Lamifiban
ORAL ANTAGONISTS:
Xemilofiban, orofiban, sibrafiban, lefradafiban.

28. Abciximab(ReoPro): Abciximab is a
monoclonal antibody that targets the GP IIb/IIIa
receptor on the surface of platelets.
Abciximab is indicated as an adjunct to
aspirin and heparin for prevention of
ischemic complications in patients
undergoing PCI. It is
also indicated for the short-term (1 month)
reduction of risk of MI in patients who have
unstable angina that is not responding to
full conventional therapy and who are to
undergo PCI. Side effects are bleeding and
thrombocytopenia

29. Eptifibatide (Integrilin): Eptifibatide is a synthetic
cyclic heptapeptide and is one
of the small-molecule GP IIb/IIIa inhibitors
It reversibly inhibits platelet aggregation by
preventing the binding of fibrinogen and other
adhesive ligands to the GP IIb/IIIa receptor.
Eptifibatide is indicated for the prevention of early MI
in patients presenting with unstable angina or non-Q-
wave MI (NSTEMI) who have had chest pain within
the last 24 hours and who have ECG changes and/or
elevated cardiac enzymes.
Tirofiban (Aggrastat): Tirofiban is a non-peptidal
antagonist of the GPIIb/IIIa receptor. . It prevents
fibrinogen from binding to the GP IIb/IIIa
receptor, thus blocking platelet aggregation. Tirofiban
is indicated for the prevention of early MI in patients
presenting with unstable angina or NSTEMI who
have had chest pain within the last 12 hours and who
have ECG changes and/or elevated cardiac

30. Anti integrin therapy:
Integrins are the foremost family of cell adhesion
molecules that regulate immune cell trafficking in
health and diseases. Different integrin antagonists
can be used in therapeutics:
1. Natalizumab(tysabri): Integrin alpha4 mediates
organ-specific migration of immune cells to the
inflamed brain, thereby playing the critical role in the
pathogenesis of multiple sclerosis. Anti-alpha4
integrin therapy (natalizumab) aiming to block
infiltration of autoreactive lymphocytes to the
inflamed brain has been validated in several clinical
trials for the treatment of multiple sclerosis. Other
potential uses of this type of therapeutic mAb include
inflammatory and/or autoimmune conditions with a
high impact in general population, including asthma
etc

31. 2. Efalizumab(raptiva): for the therapy of
moderate to severe forms of psoriasis. The other
therapeutic uses of anti-LFA-1 mAb include the
prevention of bone marrow graft failure, and the
treatment of kidney allograft rejection, asthma
3. Abciximab( ReoPro): is a humanised version
of a function-blocking mAb (7E3) that recognises
the β3 subunit and blocks the platelet fibrinogen
receptor αIIbβ3.It is used in the treatment of
unstable angina and as an adjuvant to
percutaneous coronary interventions.
4.Erlizumab(rhuMab):is a recombinant
humanized monoclonal antibody that was
an immunosuppressive drug. Erlizumab was to
treat heart attack, stroke, and traumatic shock.

32. The drug works by blocking a growth factor in
blood vessels. Specifically, erlizumab
targets CD18 and an LFA-1 integrin. Erlizumab
was meant to stop lymphocyte movement into
inflamed tissue, thereby reducing tissue damage.
5.Enlimomab: is an anti-ICAM monoclonal
antibody, inhibits leukocyte adhesion to the
vascular endothelium, thereby decreasing
leukocyte extravasation and inflammatory tissue
injury. It is beneficial in reducing both disease
activity in refractory rheumatoid arthritis and the
incidence of acute rejection after kidney and liver
allograft transplantations.