Cells Interact with Their
Cell and Molecular Biology
Lecture 7
Environment
The Extracellular
Matrix and Cell
Interactions
John Donnie A. Ramos, Ph.D.
Department of Biological Sciences
College of Science
University of Santo Tomas
Glycocalyx The Extracellular Matrix
q Cell coat
q Organized network of extracellular materials beyond the
q Carbohydrate projections on the outer surface of plasma immediate vicinity of the plasma membrane
membrane
q Plays a regulatory role in determining the shape and
q Mediates cell-cell and cell-substratum interactions activities of the cell
q Provide mechanical protection to cells
q Serve as barrier to particles moving toward the plasma
membrane
Extracellular Matrix
Chondrocyte
Red Blood Cells
Ectodermal Cell of Chick Embryo Intestinal Epithelial Cells
In vitro cultured cartilage cells
Basement Membrane Functions of the
q Basal lamina
Basement Membrane
q Example of extracellular matrix q Mechanical support for attached cells
q 50-200 nm thick q Separate adjacent tissues within an organ
q Surrounds muscle and fat cells q Barrier to the passage of macromolecules
q Underlies the basal surface of epithelial tissues q Barrier to the invasion of cancer cells
q Underlies the inner endothelial lining of blood vessels
Podocyte
Epidermis
Glomerular Basement
Basement Membrane Membrane
Capillary Lumen
Dermis
Human Kidney X-section
Human Skin X-section
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Macromolecular Organization of Collagen
the Extracellular Matrix q Fibrous glycoproteins
q High tensile strength (1 mm diameter
q Composed of similar proteins collagen can suport 10 kg weight)
q Functions as scaffolds, girders, mortar, and wire q Most abundant protein in human body
(25% of all proteins)
q Produced by fibroblasts, muscle cells
and epithelial cells.
q Trimers of collagen alpha chains
q Forms a rod-like triple helix structure
q Fibrillar collagens (types I, II, and III)
q Forms cross-links with other fibers
q Contributes to decreased elasticity of skin
and increased brittleness of bones
q Ex. tendons
q Non-fibrillar collagens (Type IV)
q Found in basement membranes
q Forms network serving as mechanical
support and as a lattice for the deposition
of substances
Collagen Proteoglycan
q Protein-polysaccharide complex
q Core protein serves as the main attachment of glycosaminoglycans (CAGs)
– disaccharides
q Chondroitin sulfate
q Keratan sulfate
q Hyalurunic acid (non-sulfated CAG)
q CAGs are arranged as A-B-A-B-A where A and B are different disaccharides
q Sulfate group of CAGs gives a negative charges which bind to cations
which bind to water molecules
Fibrillar Collagen Non-Fibrillar Collagen q Forms porous, hydrated gel filling extracellular space
(Corneal Stroma) (Basement Membrane)
q Complements the function of collagens
Diseases associated with mutations of collagens
q Osteogenesis imperfecta – extremely fragile bones, thin skin, weak
tendons (Type I collagen mutation)
q Dwarfism (Type II collagen mutation)
q Skeletal deformities (Type II collagen mutation)
q Ehler-Danlos syndrome – hyperflexible joints and highly extensible
skin (Type II collagen mutation)
q Alport syndrome - disrupted glomerular basement membrane (Type
IV collagen mutation)
Role of Fibronectin in
Fibronectin
q Linear array of distinct domains (Fn
Mammalian Embryogenesis
domains) q Fibronection guide migrating cells
q Composed of ~30 independently-folding q Neural crest cells migrate to become pigment cells of the skin (P),
Fn domains sympathetic ganglia (SpG), adrenal medulla (AdM), and the
cartilages of the embryonic skull-maxillary (Mx) and mandibular
q Binding sites for other ECM components
arches (Md)
q Binding sites for receptors q Primordial germ cells (PGC)
migrate from yolk sac to site of
q Plays an important role in cell movement gonads
(migration) during embryogenesis
q Progenitor of lymphoid cells
move to different organs
Migrating PGC along the dorsal mesentery
2
Laminins Other ECM Proteins
q Glycoproteins with 3 different polypeptide chains linked by q Tenascin
disulfide bonds organized into a cross-like arrangement.
q Large oligomeric glycoprotein
q Involved in cell migration, growth and differentiation
q Found in normal and tumor cells
q Binds to other ECM components to form interconnected networks
q Either promote or inhibit cell
responsible for strength and flexibility of basement membranes
adhesion (depending on cell
q Matrix Metalloproteinases (MMPs) enzymes that destroy ECM type)
materials
q MMPs are implicated in arthritis, multiple sclerosis, q Entactin
atherosclerosis, tooth decay, and tumor progression (metastasis). q Component of basement
membrane
q Role in early adhesion of
mammalian embryos to the
uterus lining during implantation
q Thrombospondin
q Found in matrix surrounding the
lining of mature blood vessels
q Inhibits the formation of new
blood vessels (anti-angiogenic
property)
Integrins (Interaction of cells with noncellular substrates) Integrins
q Function as receptors q Functions:
q Family of integral q Adhesion of cells
membrane proteins to substratum
present in all vertebrate q Transmission of
cells. signals
q Heterodimer (a and b q Specific binding
subunits that are site for ligand
noncovalently linked) q Associated with
q 18 different a subunits several
and 8 b subunits have cytoplasmic
been identified proteins needed
for signal
transduction
(kinases)
q Binding of ligand
to the receptor
(integrin) induces
signal transduction
Integrins and Their Ligands Blood Clots and Its Inhibitors
q Blood clots (thrombus)
which causes heart attack
or stroke is due to
aggregation of blood
platelets
q Cause by presence of RGD-
containing proteins such as
fibronogen and von
Willebrand factor.
q Can be inhibited using
RGD-containing peptides
(ex. Agrastat – anti-
thrombotic agent)
3
Cell Spreading of Focal Adhesions
Mouse Fibroblasts q Sites where cell membranes comes in contact with
substratum (~10 nm).
q Dynamic structure (can be easily disassembled)
30 mins. 2 hours q Contains clusters of integrins attached to actin filaments
1 hours 24 hours
Hemidesmosomes Cell-Cell Recognition
q Specialized adhesive
structure of cells for
attachment into basal
membranes
q Filaments contain keratins
q Diseases associated
hemidesmosomes:
q Bullous pemphigoid
q severe blistering of skin
due to leakage of fluid into
the epidermis. q Similar cells secrete signals used for
q Antibodies produced by the communication with each other
body binds to bullous q Mediators of cell-cell recognition:
pemphigoid antigens (auto-
immune disease) q Selectins
q Epidermolysis bulbosa q Some members of Immunoglobulin
q Skin blisters superfamily (IgSF)
q Caused by mutations in q Some members of integrin family
hemisdesmosomal proteins q Cadherins
including integrins
Selectins IgSF Proteins
q Integral membrane q Mostly mediating the interaction
glycoproteins of immune cells
q Recognize oligosaccharides q Others mediate non-immune
on cell surface (lectin) cells.
q Examples: NCAM (neural cell-
q Types: adhesion molecule), VCAM
q L-selectin – WBC (vascular cell-adhesion
q E-selectin – endothelial cells molecule), L1 (plays a role in
q P-selectin – platelets and neural development)
endothelial cells
q Mutation in L1 gene results to
q Mediates interaction of Fetal Alcohol Syndrome (FAS) –
WBC with epithelial cells of retardation of individuals from
blood vessels alcoholic mothers (loss of
q Plays an important role in adhesive ability)
inflammation
q Plays a role in “homing” of
blood cells
4
Cadherins Cadherins Play A Role in Epithelial-
q Transmembrane Glycoproteins
Mesenchymal Transformation
q Mediates Ca2+-dependent cell
adhesion q Aggregation of cells into
an epithelium is correlated
q Ca2+ forms bridges between
with the appearance of N-
domains
cadherin (and other cell
q Appear as dimers adhesion molecules).
q Transmits signals from ECM q During cell movement,
q Cadherin-cadherin interaction cadherin expression is low.
q With long extracellular domain
(5 tandem domains),
transmembrane domain and
short cytoplasmic domain
(associated with catenins).
q Types:
q Epithelial (E) cadherin
q Neural (N) cadherin
q Placental (P) cadherin
Cadherins in Synaptic Junctional Complex
Junctions
TJ D
AJ
Adherens Junctions Desmosomes
q Maculae adherens
q disk-shaped adhesive junctions
q ~1 µm in diameter
q Zonulae adherens
q Abundant in areas of high stress (skin, gingiva, uterine cervix)
q Common in epithelial tissues q Contains desmogleins and desmocollins
q 30 nm junction between cells q Pemphigus vulgaris (body secretes antibodies against desmogleins) –
q Contains Cadherins (Ca dependent linkages) loss of epidermal cell-cell adhesion and severe blistering of the skin
(autoimmune disease)
5
Cell Surface Interactions Tight Junctions
Mouse mammary gland epithelial cells
cultured without ECM.
Occluding
property of TJ
Mouse mammary gland epithelial cells
cultured with ECM.
q Zonulae occlulens
q Cell surface interaction plays a role in transmembrane signalling q Contains an integral protein called occludin (encircling nature)
(transfer of information across the plasma membrane) q Responsible for impermeability of some membranes (blood-brain
q Responsible a variety of processes including change in cytoplasmic barrier on endothelial cells of the brain)
pH, protein phosphorylation, gene expression, etc. q Immune cells secretes signals to open the TJ
Gap Junctions Plasmodesmata
q Specialized sites for cell
communication in animal cells
(sharing of metabolites)
q ~ 3 nm (closest distance between
two cells) – not direct contact
q Composed of integral membrane
protein called connexin which
forms a multisubunit complex
called connexon (6 connexin
subunits).
q Annulus – central openning (1.5 q Specialized sites for cell communication in plant cells (allows plant
nm in diameter) formed by the cells to function as a metabolic unit)
connexon which serves as a q Cylindrical cytoplasmic channels (30-60 nm in diameter)
communication channel between q Impermeable to substance larger than 1000 daltons (but can be
cells dilated) – some plant viruses infect using this site (using movement
protein)
q CX43 – connexin of
cardiac muscles q Lined by plasma membrane
q CX40 – connexin of q Desmotubule – dense central structure from ER
cardiac nerves q Annulus – the passageway for plasmodesmata
Plant Cell Wall Plant Cell Wall
Functions:
q Responsible for shape of
cells
q Mechanical support (for the
cell and the plant) q Can be digested using cellulase (resulting cell is called protoplast)
q Protection from damage, q Microfibrils – organization of cellulose molecules (60 nm in diameter)
q Composed of bundles of 40-60 cellulose molecules
mechanical abrasion,
osmotic influx of water, q Crosslinking of microfibrils are at 90°
pathogens q Macromolecules found on the matrix of cell wall:
q Hemicellulose – branched polysaccharides; binds to surfaces of cellulose
q Mediate cell-cell interaction microfibrils
q Primary barrier for q Pectins – negatively charged polysaccharides; holds water molecules
substances (forms hydrated gels); defensive response of plant cells
q Structural proteins – determines the architecture of cell walls
q Originates as a cell plate
q Deposition of lignin (secondary walls) – for structural support
6
Cell Adhesion in Inflammation Cell Adhesion in Metastasis
q Cancer is the result of
abnormal cell proliferation.
q The spread of a tumor to other
parts of the body is called
metastasis.
q Metastatic cells have special
cell adhesion properties:
Movement of neutrophils during inflammation
q Are less adhesive (loss of e-
cadherin)
q Inflammation is a response to infection or injury but can be q Are able to penetrate several
triggered inappropriately. barriers.
Steps leading to metastatic spread
q Inflammatory response: q Are able to invade normal
q Recruitment of leukocytes to site of injury. tissues
q Neutrophils attach to P- and E-selectins. q Degradation of extracellular
matrix by MMPs
q Neutrophils start to “roll” along wall of vessel.
q Chemokines attract inflammatory cells
