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Transcript
Cell adhesion
Láng, Orsolya MD, PhD
Dept. Genetics, Cell & Immunobiology, Semmelweis University
Lecture EPh 2014
www.dgci.sote.hu
Cell adhesion
Contact with other cells and extracellular matrix
Role:
- embryonic development: formation of layers,
tubes
- connection and communication between cells
- barrier, membrane polarity, mechanical
attachment
- cell motility
- signal transduction
- cancer progression
Cell-cell adhesion molecules
1. Cadherins
2. CAMs or Ig like adhesion
molecules
Cell-ECM adhesion Molecules
4. Integrins
5. Proteoglycans (dystroglycan)
3. selectins
Homophyl or heterophyl
Ion dependency :Ca++, Mg++
Cytoskeletal component
Junctional complex
Cadherins
 Homophil connection
 Cell – cell
 Ca++ - dependent binding
 I.c. anchored to actin or intermedier
filamentum
 Significant role in development
of vertebrates
 Cell specificity
N – neural
P – placental
E - epithelial
Cadherin superfamily
classical
Non-cl
Type
Localisation
Adherent
E
Epithelial
Adherens junction
N
Neuronal, muscle,
fibroblast
Adherens junction
Synapsism
P
Placenta, epidermis,
mammary gland
Adherens junction
VE
Endothelial
Adherens junction
Desmocollin
Skin
Desmosomes
Desmoglein
Skin
Desmosomes
T cadherin
Neuronal, muscle
-
Cadherin 23
Inner ear
Stereocilia
Cadherins allow cells to sort themselves
Ig-like adhesion molecules
 Homophil connection - typical
 Heterophil connection - rare
5 pcs. Ig-type domain
 Ca 2+ indep. adhesion
Linked to actin filaments
More than 20 variations
 Expressed in the critical phase
of development
 Tissue-specificity:
N-CAM - neuron
L-CAM – liver
V-CAM1- vascular
Intracellular
In melanoma – relation between
ICAM-1 density and the
metastatic activity of the tumor
Selectin molecules
Lectin type proteins,
Carbohydrate specificity
Tissue-specificity:
E - epithelial
L - lymphoid
P - placenta
L selectin: it has role in the initial phase of
adhesion;
in newborns the level of L sel. is low – the
low number of inflammations (?!)
Integrin molecules
 Heterophil connection
Ca2+-dependent binding
Focal contacts
 Its i.c. linker proteins are
i.e.. talin, a-actinin, vinculin
 RGD sequ. is significant in
ECM binding
 Partner molecules:
fibronectin
laminin
collagen
Deficiency (b) – the adhesion of
leukocytes affected, results
the increase of inflammations
Type of integrins
Integrin
Ligand
Localisation
Mutation of α or ß subunit
α5ß1
fibronectin
ubiquitous
Early death of the embryo,
α6ß1
laminin
ubiquitous
Early death of the embryo, severe skin
blistering
α7ß1
laminin
muscle
Musclar dystrophy
αLß2
ICAM
leukocytes
Impaired recruitment of leukocytes, LAD,
recurrent infections
αIIbß3
fibrinogen
thrombocyte
bleeding, no platelet aggregation,
(osteoporosis)
α6ß4
laminin
Hemidesmosome
epithelial cells
severe skin blistering
Role of adhesion molecule in extravasation of
leukocytes
Adhesion molecules
www.cbrinstitute.org/.../media/image1.html
Functional classification of cell junction
Functional classification of cell junction
Anchoring – mechanical junction
Barrier formation - separation
Channel like (gap junction) – communication
Signal relaying junctions
sinapsm
immunological sinapsism
transmembrane proteins
Anchoring junctions
Junctional complexes
 Tight junction
 Zonula adherens
 Desmosome
 Gap junction
Interdigitation
Hemidesmosome
Tight junction(TJ) = zonula occludens
 Isolate parts of plasma membrane (apical and basolateral)
 Completely encircle polarized cells
 Look like honey comb
Molecular structure of tight junction
Claudins and occludins (membrane proteins) zip
two membranes together
Stabilized by spectrin
Connected to spectrin by adapter proteins
ZO1 and ZO2
Regulation of tight junctions
 Belts of proteins that close extracellular space between cells
 Prevent passage of water and water-soluble substances
 Account for electrical resistance across epithelia
 Leaky epithelia where there is need for some traffic
Hormones
Vasopressin
Cytokines
Lack of ATP causes “leak”
Extravasating leukocytes open tight junctions
Tight junctions separate components of the plasma membrane as well
Mechanical juncion: zonula adherens - adhesion belt
Adherent junctions
Hold cells tightly together
Confer mechanical strength
Common in tissue that are subject to severe
stress such as skin and cardiac muscle
Molecular structure of zonula adherens
 Belt like junctions located just below tight
junction
 Simple points of attachment, do not contain
channels connecting the interiors of the two
attached cells
 Adhesion molecule -cadherin (E)
 Linker proteins - α, b and  catenin, vinculin
 Cytoskeletal component - microfilament
(actin)
Desmosome = macula adherens
Adhesion molecule
cadherins
Cytoskeletal component
Intermedier filaments
(i.e. keratin)
Cytoplasmatic
plaque
Components of desmosomes
The expression pattern of
DSGs and DSC is tissuespecific and may even
vary within one tissue,
like in the different layers
of the epidermis
Spinous layer
desmosome
Hemidesmosome – Cell-ECM junction
Fixing of epithelial cells
to the basal membrane
Focal adhesion
Adhesion molecule - integrins
/Linker proteins – plectin, dystonin/
Cytoskeletal component – intermediate filament
(keratin)
Desmosomes and hemidesmosomes
both link to intermediate filaments
Gap junction – channel forming junction
Communicating junction
100-1000 connexon
protein: connexin
homomeric-heteromeric
combinations
Gap junction
TEM
SEM
In plant cells plasmodesmata perform many of the same
functions as gap junctions
Interdigitation
Wave-like plasma membrane extensions + desmosomes
Characteristic of epithelial cell
nucleus
Basal striation
Increases the surface of the basal membraen
for molecular transport
Basal striation
mitochondria
Basement
membrane
ECM- Extracellular matrix
• Mechanical
• Influence on migration of the cells
• Regulation of activity of molecules released
• Co-receptors
Main components of ECM
Protein component
Glycan
Laminin (LN)
LNs are cross-shaped proteins.
All LN isoforms contain α, β1 and β2 chains that are connected by
disulfide bonds (18 isoform of laminin- diverse in tissue)
LN binds to membrane receptors (integrins) of the overlying cells.
LN attaches cells to the basal lamina.
LN contains binding sites for other components of the basal
lamina: type IV collagen, heparin,
Molecular Biology of the Cell (© Garland Science 2008)
Collagens
 Provide strength of ECM
maintains form of tissue
 Most abundant protein in vertebrates
 Found as bundles throughout ECM
 Structure:
 Rigid triple helix of 3 intertwined polypeptide chains
 Unusual aa compositionn (hydroxilation)
 Collagen fiber consists of numerous fibrils (molecules, polypeptides)
Structure and synthesis of collagene
 ER/Golgi: Pro-a-chains are produced,
hydroxylated and glycosylated at selected
Lys and Pro residues.
 The lack of vitamin C prevents hydroxylation →
impaired fibril formation (scurvy).
Processed pro-peptides assemble into triplehelical pro-collagen.
 Golgi: Disulphide bonds form between the Nand C-termini of procollagen.
 After exocytosis, N- and C-termini are trimmed,
allowing fibril assembly
 Fibrils (diam.10-300 nm)
 More than 15 types
 I., II., III., V., XI. – formation of fibrils
 IV., VII. – network
 IX., XII. – association of fibrils
Collagen Assembly
Matrix types produced by vertebrate cells
Anchor
C
O
L
L
A
G
E
N
E
I
II
III
Proteogly.
Receptor
Cells
fibronectin
ChS, DS
ChS
HS, Hep.
fibroblast
chondrocyte
hepatocyte
epithel
integrin
IV
laminin
HS, Hep.
laminin rec.
V
VI
fibronectin
fibronectin
HS, Hep.
HS
integrin resting fibrobl.
integrin resting fibrobl.
epithel,
endothel,
regenerating
hepatocyte
Abbr.: ChS – chondroitin sulfate; DS – dermatan sulfate;
HS – heparan sulfate; Hep - heparin
Fibroblast surrounded by collagen fibrils
Osteogenesis imperfecta – clinical
manifestation
Tissue elasticity
Elastin
 Elastic fibers permit long-range
deformability and passive recoil.
 Elastic modulus is ~0.1 MPa.
 This function is crucial for arteries, lung,
skin and other dynamic connective tissues
that undergo cycles of extension and
recoil.
 The major component of elastic fibers is
the thread-like protein elastin
 Fibrillins provide an outer structure for
amorphous, cross-linked elastin.
 During ageing, elastin is degraded and
becomes inflexible.
Tropoelastine→ cross link→ functional elastin
Fibronectin
 Glycoproteins
 Fibronectin is a dimer of two identical 250 kDa subunits
 Alternative splicing of one gene produces ~20 human FNs
 RGD (Arg-Gly-Asp) component is recognised by integrines
 Mediate the connection between the ECM and the cell membrane.
 FN exists as a soluble form (plasma FN) and cellular FN.
Plasma FN is predominantly produced in the liver.
Cellular FN is deposited into the ECM by a cell-mediated process,
 FN binds a variety of other proteins like integrins, heparin, collagen, fibrin.
TEM structure of basal lamina ~ basement membrane
In epithelial membrane – prevent cancer cell invasion
Kidney – serves as a filtration barrier
Molecular Biology of the Cell (© Garland Science 2008)
Molecular structure of basal lamina
Transmembrane
Molecular Biology of the Cell (© Garland Science 2008)
Structure of Hyaluronan
 HA is a large, unbranched and negatively charged polymer of repeating (225K) disaccharides.
 it is synthesized freely at the plasma membrane by hyaluronan synthases.
 Free HA is found in the ECM of migrating cells.
 HA binds to cell surface receptors
 (CD44)
 HA binds proteoglycans.
Structure of aggrecan aggregate
In cartilage the key proteoglycan is
aggrecan (MW: 2 x 108)
At 40 nm intervals aggrecan core
proteins are attached (assisted by a
linker protein) to a decasaccharide
sequence in hyaluronan
Attached to the aggrecan core
protein are multiple GAGs
The major GAGs in aggrecan are
chondroitin sulphate and keratin
sulphate
Aggrecan
Rheumatoid artritis
Synovial fluid
Serum
Fimbrin
Nexilin
Molecular structure of the focal contact
Tensin
α-Actinin
Talin
Paxillin
Caveolin
Zyxin
Palladin
Vinexin
Ponsin
Integrin, Syndecan-4, Leukocyte common antigen
Function of the adhesion molecules
Adhesion molecule
Summary I.
Summary II.
Molecular Biology of the Cell (© Garland Science 2008)