Cell adhesion molecules (CAMs) are essential glycoproteins that facilitate cell interactions and tissue formation in the body. They play crucial roles in various biological processes, including inflammation, cancer metastasis, and wound healing, with different types categorized into families such as cadherin, integrin, selectin, and the immunoglobulin superfamily. Abnormal functioning of these molecules can lead to diseases like breast cancer, leukocyte adhesion deficiency, and other epithelial cancers.

1. CELL ADHESION
MOLECULES
Dr.N.Manjula

2. INTRODUCTION
 Cells in vivo must form contacts with their neighbour
cell or with ECM in order to form tissues.
 The tissues of our body are held together by
molecular interaction between the cells.
 CAM are glycoproteins located on the cell surface.
 These proteins are typically trans membrane
receptors but are sometimes stored in cytoplasm.
 CAM are also important for recruitment of leukocytes
to site of inflammation by promoting cell – cell and cell
– matrix interactions.

3.  CAM bind with other cells by Cell Adhesion
Receptor.
 These receptors enable cells to recognize and
bind molecules on other cells or ECM.
 They form two type of adhesion:-
 HOMOPHILIC: between same type of molecules.
 Eg: cadherin – cadherin.
 HETEROPHILIC:- between different type of
molecules.
 Eg: selectin – mucin.

5. CLASSIFICATION
 Most of CAM belong to four protein family:
 Cadherin
 Integrin
 Selectin
 Ig Super Family [IgS]

7. CADHERIN
 They are calcium dependent adhesion molecules.
 This family has almost 90 members which participate
in interaction between cells of same type.
 Subclasses:-
 N – cadherin – neural.
 P – cadherin – placental.
 E – cadherin – epithelial.
 They exhibit homophilic adhesion.
 Failure of cadherin mediated cell – cell adhesion
is seen in breast cancer.

8.  Interactions between cadherin connect plasma
membrane of adjacent cells forming two types of
cell junction:
 1.ZONULA ADHERENS: small, spotlike, junction
located near apical surface of epithelial cells.
 2.DESMOSOMES: stronger and more extensive
junctions present in epithelial and muscle cells.
 Migration of keratinocytes in re-epithelialization of
skin wound healing is depend on desmosomal
junction.

9.  Linkage of cadherin with cytoskeleton occurs via
two classes of catenin.
 Beta and Alpha.
 Cell to cell interaction mediated by cadherin and
catenins play major role in regulating cell motility,
proliferation and differentiation.

10.  Dimnished function of E cadherin contributes to
certain cancer that includes breast and gastric
cancers.
 Free beta catenin acts independently of cadherin
in Wnt signaling pathway which participates in
stem cell homeostasis and regeneration.
 Mutation and altered expression of Wnt/beta
catenin pathway is implicated in cancer
development particularliy in GIT and Liver.

12. Ig Super Family [IgS]
 They are calcium independent CAM.
 They exhibit both homophilic and heterophilic
adhesion.
 Involved in recognition, binding, adhesion process.
 They possess an extracellular region known as
immunoglobulin domain.

13.  Adhesion molecules that contain variable number
of immunoglobulin like domain are member of this
family.
 Few of them are: - ICAM – 1 (CD54), ICAM – 2
(CD102), ICAM – 3 (CD50), and VCAM (CD106)
expressed on vascular endothelial cells bind to
integrin molecules.

14.  MAdCAM – 1 has both Ig like domain and mucin
like domain.
 It is expressed on mucosal endothelium and
directs lymphocyte entry into mucosa.
 It binds to integrin alpha4beta7 (LPAM) via Ig like
domain and to L – selectin (CD62L) via mucin like
domain.

15.  Platelet endothelial cell adhesion molecule
{PECAM – 1, CD31}is found on surface of
leukocytes.
 It exhibits homotypic binding { PECAM – PECAM}.
 Junctional cell adhesion molecule (JAM – 1,CD
321) is located within endothelial junctional
complex.
 Take part in transendothelial migration.

16. ICAM 1
 Intercellular adhesion molecule 1 is expressed on
endothelial cells.
 When there is an invading pathogen, the
endothelial cells become activated and will
express ICAM 1 on their surfaces.
 ICAM 1 will bind to cell adhesion molecule LFA 1
(lymphocyte function associated 1 - integrin)
molecule expressed on monocytes.
 Monocytes will move across the endothelial cells
to the interstitial space to differentiate to
macrophage.

17. VCAM 1
 It is expressed on endothelial cells.
 When there is an invading pathogen, the
endothelial cells become activated and will
express VCAM 1 on their surfaces.
 VCAM 1 will bind to CAM - VLA 4 (very late
antigen 4 – integrin ) expressed on monocytes.
 Monocytes will move across endothelial cells to
the interstitial space to differentiate to
macrophage.

19.  It is a family of membrane glycoprotein which has
an extracellular lectin like domain that enable
these molecules to bind to specific carbohydrate
groups.
 Selectin primarily interact with sialylated
carbohydrate moiety called sialyl – Lewis which is
often linked to mucin like molecules.
 P – selectin is stored within Weibel – Palade
bodies, atype of granule within endothelial cell.

20. SELECTIN
 They are divalent cation dependent CAM
 They are carbohydrate binding proteins.
 Eg: E – selectin [endothelial].
 L – selectin [leukocyte].
 P – selectin [platelet].
 Play major role in many host defense mechanism.

21.  On activation of endothelial cell, the granule fuses
with plasma membrane, resulting in expression of
P – selectin on the cell surface.
 Expression of E – selectin requires synthesis of
new protein and occur after endothelium has been
stimulated by pro inflammatory cytokines.
 These are responsible for initial stickiness of
leukocytes to vascular endothelium.

22.  P - selectin
 Recruitment of neutrophils.
 Type 1 activation.
 Induced by histamine in minutes.
 E – selectin
 Type 2 activation.
 Takes hours.
 L – selectin
 Allows naïve T lymphocytes to move from blood
into lymph node.

23. Increased levels of E selectin
 Scleroderma
 polyarteritis nodosa
 SLE
 Psoriasis
 Atopic dermatitis

24. INTEGRIN
 They are large group of heterodimeric glycoprotein
 Alpha and Beta both group participate in binding.
 They take part in cell – cell adhesion, binding,
interaction of cell with ECM.
 These are heterodimeric proteins consisting of
alpha and beta chain that are noncovalently
associated at the cell surface.

25.  Most integrins bind to ECM and provide cell matrix
interactions throughout the body.
 Some subfamilies are involved in cell to cell
interactions.
 Integrin bind to ECM proteins such as fibronectin,
laminin, osteopontin providing connection
between cells and ECM and also to adhesive
proteins in other cells establishing cell to cell
contact.

26.  FIBRONECTIN is a large protein that bind to
many molecules such as collagen, fibrin,
proteoglycan, and cell surface receptors.
 The plasma form binds to fibrin, helping to
stabilize blood clot that fills gap created by wound.
 Thus helps in formation of provisional matrix in
wound healing.

27.  LAMININ is the most abundant glycoprotein in
basement membrane.
 It has binding domain for both ECM and cell
surface receptors.
 It also mediates attachment of cells to connective
tissue substrates.

28.  Cadherin and Integrin link the cell surface with
cytoskeleton through binding to actin and
intermediate filaments.
 Ligand binding to integrin causes clustering of
receptors in cell membrane and formation of
focal adhesion complexes.

29.  Integrin - cytoskeleton complex function as
activated receptors and trigger number of signal
transduction pathway including MAP kinase, PKC,
PI3K pathway which are also activated by growth
factors.
 Integrin and growth factor receptor ineract [cross –
talk] to transmit environmental signals to the cell
that regulate proliferation, apoptosis,
differentiation.

30.  Leukocytes express special type of integrin
known as beta2 integrin or CD 18.
 Integrin with beta 2 subunit bind to members
of Ig superfamily.
 Some integrins must be activated before they
can bind with high affinity to their ligands.

31.  Clustering of integrin on the cell surface also
increases the likelihood of effective binding and
plays a role in leukocyte migration.
 Lack of this role of integrin leads to LEUKOCYTE
ADHESION DEFICIENCY [LAD type 1] AR.
 Characterized by recurrent bacterial infection and
impaired wound healing.
 Similar deficiency with impaired expression of
selection is termed as [LAD type 2].

32. DISEASES RELATED TO INTEGRIN DEFICIENCY
 There are three inherited autosomal recessive
disorders associated with integrin.
 1.mutation in alpha 2 b and beta 3 subunit =
GLANZMANN’S THROMBASTHENIA [ platelet
dysfunction and bleeding disorder]
 2.point mutation and gene deletion in beta 2 =
LAD.
 3.mutation in alpha 6 and beta 4 = JUNCTIONAL
EPIDERMOLYSIS BULLOSA skin blistering.

34. ROLE OF CELL ADHESION MOLECULE IN:
 Cell to cell interactions.
 Embryogenesis.
 Immunity – migration of cells to
inflammation site.
 Cell – tissue – organ development.
 Wound healing.
 Cancer metastasis.

39. EMBRYOGENESIS

40. IN CANCER
 E cadherin has been shown to be a potent
invasion suppressor as well as tumor suppressor.
 Disturbed expression profiles of
E-cadherin/catenin complex have been
demonstrated in histological section of many
human tumor types.
 Majority of carcinoma seems to show deregulated
E-cadherin expression by various mechanism.

41.  The predominant mechanism emerging in
most carcinoma or hypermethylation of E-
cadherin promoter and expression of
transrepressor molecules such as SIP1, Snail
, Slug that bind sequence elements in the
proximal E-cadherin promoter.
 Loss of E cadherin function elicit active signal
that supports migration, invasion, metastasis
of tumor cells.
 Loss E cadherin correlates poor prognosis.

43. THERAPEUTIC USES
 In osteoporosis E selectin tagged stem cells
help migrate osteoblast developed from bone
marrow to site needed.

44. Tensin in health and disease
 Tensin is a cytoplasmic phosphoprotein that is
localised to integrin mediated focal adhesion.
 It binds to actin filaments at ABD domain and
contains phosphotyrosine binding PTB domain
which interacts with the cytoplasmic tail of
integrin.
 In addition tensin has Src Homology 2(SH2)
domain capable of interacting with tyrosine
phosphorylated proteins

45. Role of tensin in carcinogenesis
 Tensins are deregulated in cancer although their
function is tissue dependent.
 Cten Tensin 4 acts as tumour suppressor in
prostate and as oncogene in colon, breast and
lung neoplasia.
 Tensin 1 and 3 found to downregulate in prostate,
breast,kidney and skin cancer.
 Tensin 2 is down regulated in kidney and lung
cancer but over expressed in hepatocellular
carcinoma

46.  Thus tensin function as a platform for assembly of
signalling complexes at focal adhesions by
recruiting tyrosine phosphorylation signalling
molecules through the SH 2 domain and also by
providing interaction sites for other SH2
containing proteins.
 Therefore, tensin and its downstream signalling
molecules may be targets for therapeutic
intervention in renal disease , wound healing and
cancer.

47.  The processes of organogenesis, organ
homeostasis and repair require modulation of
cell adhesion to enable cell motility and maintain
cell stasis.
 Cell adhesion can be viewed as intercellular
adhesion (i.e. adhesions between cells) or cell-
to-matrix adhesion.
 The former is maintained through intercellular
junctions, while the latter is maintained
predominantly through focal adhesions.

48. Summary
 Special interaction between molecules expressed
on the surface of leukocytes (receptor) and
molecule on the surface of potential target cells
(ligands) are important mechanism in cell - cell
communication.
 These surface molecules are collectively called as
cell adhesion molecules
 Despite of their various role, malfunctioning of
CAM leads to breast cancer, leukocyte adhesion
deficiency syndrome, epithelial cell cancer.

49. References
 Kuby book of immunology 6 th edition.
 Robbins pathologic basis of disease.
 Recent advances in histopathology no 23.