Chapter 15
The extracellular matrix and cell
adhesion
By
George Plopper
15.1 Introduction
• Cell-cell junctions are specialized protein
complexes that allow neighboring cells to:
– adhere to one another
– communicate with one another
• The extracellular matrix is a dense network of
proteins that:
– lies between cells
– is made by the cells within the network
15.1
Introduction
• Cells express receptors for extracellular
matrix proteins.
• The proteins in the extracellular matrix
and cell junctions control:
– the three-dimensional organization of cells
in tissues
– the growth, movement, shape, and
differentiation of these cells
15.2 A brief history of research on the
extracellular matrix
• The study of the extracellular matrix and cell
junctions has occurred in four historical
stages.
– Each is defined by the technological advances
that allowed increasingly detailed examination of
these structures.
• Current research in this field is focused on
determining how the proteins in the
extracellular matrix and cell junctions control
cell behavior.
15.3 Collagen provides structural support
to tissues
• The principal function of collagens is to
provide structural support to tissues.
• Collagens are a family of over 20
different extracellular matrix proteins.
– Together they are the most abundant
proteins in the animal kingdom.
15.3 Collagen provides structural support to
tissues
• All collagens are organized into triple
helical, coiled-coil “collagen subunits.”
– They are composed of three separate
collagen polypeptides.
• Collagen subunits are:
– secreted from cells
– then assembled into larger fibrils and fibers
in the extracellular space
15.3 Collagen provides structural support to
tissues
• Mutations of collagen genes can lead to
a wide range of diseases, from mild
wrinkling to brittle bones to fatal
blistering of the skin.
15.4 Fibronectins connect cells to
collagenous matrices
• The principal function of the
extracellular matrix protein fibronectin is
to connect cells to matrices that contain
fibrillar collagen.
• At least 20 different forms of fibronectin
have been identified.
– All of them arise from alternative splicing of
a single fibronectin gene.
15.4 Fibronectins connect cells to collagenous
matrices
• The soluble forms of fibronectin are
found in tissue fluids.
• The insoluble forms are organized into
fibers in the extracellular matrix.
15.4 Fibronectins connect cells to collagenous
matrices
• Fibronectin fibers consist of crosslinked
polymers of fibronectin homodimers.
• Fibronectin proteins contain six
structural regions.
– Each has a series of repeating units.
15.4 Fibronectins connect cells to collagenous
matrices
• Fibrin, heparan sulfate proteoglycan,
and collagen:
– bind to distinct regions in fibronectin
– integrate fibronectin fibers into the
extracellular matrix network
• Some cells express integrin receptors
that bind to the Arg-Gly-Asp (RGD)
sequence of fibronectin.
15.5 Elastic fibers impart flexibility to
tissues
• The principal function of elastin is to
impart elasticity to tissues.
• Elastin monomers (known as
tropoelastin subunits) are organized into
fibers.
– The fibers are so strong and stable they
can last a lifetime.
15.5 Elastic fibers impart flexibility to
tissues
• The strength of elastic fibers arises from
covalent crosslinks formed between
lysine side chains in adjacent elastin
monomers.
• The elasticity of elastic fibers arises
from the hydrophobic regions, which:
– are stretched out by tensile forces
– spontaneously reaggregate when the force
is released
15.5 Elastic fibers impart flexibility to
tissues
• Assembly of tropoelastin into fibers:
– occurs in the extracellular space
– is controlled by a threestep process
• Mutations in elastin give rise to a variety
of disorders, ranging from mild skin
wrinkling to death in early childhood.
15.6 Laminins provide an adhesive
substrate for cells
• Laminins are a family of extracellular
matrix proteins.
– They are found in virtually all tissues of
vertebrate and invertebrate animals.
• The principal functions of laminins are:
– to provide an adhesive substrate for cells
– to resist tensile forces in tissues
15.6 Laminins provide an adhesive substrate for
cells
• Laminins are heterotrimers comprising
three different subunits wrapped
together in a coiled-coil configuration.
• Laminin heterotrimers do not form
fibers.
– They bind to linker proteins that enable
them to form complex webs in the
extracellular matrix.
15.6 Laminins provide an adhesive substrate for
cells
• A large number of proteins bind to
laminins, including more than 20
different cell surface receptors.
15.7 Vitronectin facilitates targeted cell
adhesion during blood clotting
• Vitronectin is an extracellular matrix protein.
– It circulates in blood plasma in its soluble form.
• Vitronectin can bind to many different types of
proteins, such as:
–
–
–
–
–
collagens
integrins
clotting factors
cell lysis factors
extracellular proteases
15.7 Vitronectin facilitates targeted cell adhesion during blood
clotting
• Vitronectin facilitates blood clot
formation in damaged tissues.
• In order to target deposition of clotting
factors in tissues, vitronectin must
convert from the soluble form to the
insoluble form, which binds clotting
factors.
15.8 Proteoglycans provide hydration to
tissues
• Proteoglycans consist of a central protein
“core” to which long, linear chains of
disaccharides, called glycosaminoglycans
(GAGs), are attached.
• GAG chains on proteoglycans are negatively
charged.
– This gives the proteoglycans a rodlike, bristly
shape due to charge repulsion.
15.8 Proteoglycans provide hydration to
tissues
• The GAG bristles act as filters to limit
the diffusion of viruses and bacteria in
tissues.
• Proteoglycans attract water to form gels
that:
– keep cells hydrated
– cushion tissues against hydrostatic
pressure
15.8 Proteoglycans provide hydration to
tissues
• Proteoglycans can bind to a variety of
extracellular matrix components,
including:
– growth factors
– structural proteins
– cell surface receptors
• Expression of proteoglycans is:
– cell type specific
– developmentally regulated
15.9 Hyaluronan is a glycosaminoglycan
enriched in connective tissues
• Hyaluronan is a glycosaminoglycan.
– It forms enormous complexes with
proteoglycans in the extracellular matrix.
• These complexes are especially
abundant in cartilage.
– There, hyaluronan is associated with the
proteoglycan aggrecan, via a linker protein.
15.9 Hyaluronan is a glycosaminoglycan enriched in connective
tissues
• Hyaluronan is highly negatively
charged.
– It binds to cations and water in the
extracellular space.
• This increases the stiffness of the extracellular
matrix .
• This provides a water cushion between cells
that absorbs compressive forces.
• Hyaluronan consists of repeating
disaccharides linked into long chains.
15.9 Hyaluronan is a glycosaminoglycan enriched in connective
tissues
• Unlike other glycosaminoglycans,
hyaluronans chains are:
– synthesized on the cytosolic surface of the plasma
membrane
– translocated out of the cell
• Cells bind to hyaluronan via a family of
receptors known as hyladherins.
– Hyladherins initiate signaling pathways that
control:
• cell migration
• assembly of the cytoskeleton
15.10 Heparan sulfate proteoglycans are
cell surface coreceptors
• Heparan sulfate proteoglycans are a subset
of proteoglycans.
– They contain chains of the glycosaminoglycan
heparan sulfate.
• Most heparan sulfate is found on two families
of membrane-bound proteoglycans:
– the syndecans
– the glypicans
15.10 Heparan sulfate proteoglycans are cell surface
coreceptors
• Heparan sulfates are composed of
distinct combinations of more than 30
different sugar subunits.
– This allows for great variety in heparan
sulfate proteoglycan structure and function.
• Cell surface heparan sulfate
proteoglycans:
– are expressed on many types of cells
– bind to over 70 different proteins
15.10 Heparan sulfate proteoglycans are cell surface
coreceptors
• Cell surface heparan sulfate
proteoglycans
– assist in the internalization of some
proteins
– act as coreceptors for:
• soluble proteins such as growth factors
• insoluble proteins such as extracellular matrix
proteins
• Genetic studies in fruit flies show that
heparan sulfate proteoglycans function
in:
– growth factor signaling
15.11 The basal lamina is a specialized
extracellular matrix
• The basal lamina is a thin sheet of
extracellular matrix
– is composed of at least two distinct layers
– is found at:
• the basal surface of epithelial sheets
• neuromuscular junctions
15.11 The basal lamina is a specialized extracellular
matrix
• The basement membrane consists of
the basal lamina connected to a
network of collagen fibers.
• The basal lamina functions as:
– a supportive network to maintain epithelial
tissues
– a diffusion barrier
– a collection site for soluble proteins such
as growth factors
– a guidance signal for migrating neurons
15.11 The basal lamina is a specialized extracellular
matrix
• The components of the basal lamina
vary in different tissue types.
• But most share four principal
extracellular matrix components:
– sheets of collagen IV and laminin are held
together by:
• heparan sulfate proteoglycans
• the linker protein nidogen
15.12 Proteases degrade extracellular
matrix components
• Cells must routinely degrade and
replace their extracellular matrix as a
normal part of
– development
– wound healing
15.12 Proteases degrade extracellular matrix
components
• Extracellular matrix proteins are
degraded by specific proteases, which
cells secrete in an inactive form.
• These proteases are only activated in
the tissues where they are needed.
• Activation usually occurs by proteolytic
cleavage of a propeptide on the
protease.
15.12 Proteases degrade extracellular matrix
components
• The matrix metalloproteinase (MMP)
family is one of the most abundant
classes of these proteases.
– It can degrade all of the major classes of
extracellular matrix proteins.
• MMPs can activate one another by
cleaving off their propeptides.
– This results in a cascade-like effect of
protease activation that can lead to rapid
degradation of extracellular matrix proteins.
15.12 Proteases degrade extracellular matrix
components
• ADAMs are a second class of proteases
that degrade the extracellular matrix.
• These proteases also bind to integrin
extracellular matrix receptors.
– Thus, they help regulate extracellular
matrix assembly and degradation.
15.12 Proteases degrade extracellular matrix
components
• Cells secrete inhibitors of these
proteases to protect themselves from
unnecessary degradation.
• Mutations in the matrix
metalloproteinase-2 gene give rise to
numerous skeletal abnormalities in
humans.
– This reflects the importance of extracellular
matrix remodeling during development.
15.13 Most integrins are receptors for
extracellular matrix proteins
• Virtually all animal cells express
integrins.
– They are the most abundant and widely
expressed class of extracellular matrix
protein receptors.
• Some integrins associate with other
transmembrane proteins.
15.13 Most integrins are receptors for extracellular matrix
proteins
• Integrins are composed of two distinct
subunits, known as α and β chains.
• The extracellular portions of both chains
bind to extracellular matrix proteins
• The cytoplasmic portions bind to
cytoskeletal and signaling proteins.
15.13 Most integrins are receptors for extracellular matrix
proteins
• In vertebrates, there are many α and β
integrin subunits.
– These combine to form at least 24 different
αβ heterodimeric receptors.
• Most cells express more than one type
of integrin receptor.
– The types of receptor expressed by a cell
can change:
• over time or
• in response to different environmental
conditions
15.13 Most integrins are receptors for extracellular matrix
proteins
• Integrin receptors bind to specific amino
acid sequences in a variety of
extracellular matrix proteins.
• All of the known sequences contain at
least one acidic amino acid.
15.14 Integrin receptors participate in cell
signaling
• Integrins are signaling receptors that
control both:
– cell binding to extracellular matrix proteins
– intracellular responses following adhesion
• Integrins have no enzymatic activity of
their own.
– Instead, they interact with adaptor proteins
that link them to signaling proteins.
15.14 Integrin receptors participate in cell
signaling
• Two processes regulate the strength of
integrin binding to extracellular matrix
proteins:
– affinity modulation
• varying the binding strength of individual
receptors
– avidity modulation
• varying the clustering of receptors
15.14 Integrin receptors participate in cell
signaling
• Changes in integrin receptor
conformation are central to both types
of modulation.
• They can result from changes:
– at the cytoplasmic tails of the receptor
subunits or
– in the concentration of extracellular cations
15.14 Integrin receptors participate in cell
signaling
• In inside-out signaling, changes in
receptor conformation result from
intracellular signals that originate
elsewhere in the cell.
– For example, at another receptor
• In outside-in signaling, signals initiated
at a receptor are propagated to other
parts of the cell.
– For example, upon ligand binding
15.14 Integrin receptors participate in cell
signaling
• The cytoplasmic proteins associated with
integrin clusters vary greatly depending on:
– the types of integrins and extracellular matrix
proteins engaged.
• The resulting cellular responses to integrin
outside-in signaling vary accordingly.
• Many of the integrin signaling pathways
overlap with growth factor receptor pathways.
15.15 Integrins and extracellular matrix
molecules play key roles in development
• Gene knockout by homologous
recombination has been applied in mice
to;
– over 40 different extracellular matrix
proteins
– 21 integrin genes
• Some genetic knockouts are lethal,
while others have mild phenotypes.
15.15 Integrins and extracellular matrix molecules play key roles in
development
• Targeted disruption of the β1 integrin
gene has revealed that it plays a critical
role in:
– the organization of the skin
– red blood cell development
15.16 Tight junctions form selectively
permeable barriers between cells
• Tight junctions are part of the junctional
complex that forms between adjacent
epithelial cells or endothelial cells.
• Tight junctions regulate transport of
particles between epithelial cells.
15.16 Tight junctions form selectively permeable barriers
between cells
• Tight junctions also preserve epithelial
cell polarity by serving as a “fence.”
– It prevents diffusion of plasma membrane
proteins between the apical and basal
regions.
15.17 Septate junctions in invertebrates
are similar to tight junctions
• The septate junction:
– is found only in invertebrates
– is similar to the vertebrate tight junction
• Septate junctions appear as a series of
either straight or folded walls (septa)
between the plasma membranes of
adjacent epithelial cells.
15.17 Septate junctions in invertebrates are similar to tight
junctions
• Septate junctions function principally as
barriers to paracellular diffusion.
• Septate junctions perform two functions
not associated with tight junctions:
– they control cell growth and cell shape
during development.
• A special set of proteins unique to septate
junctions performs these functions.
15.18 Adherens junctions link adjacent
cells
• Adherens junctions are a family of
related cell surface domains.
– They link neighboring cells together.
• Adherens junctions contain
transmembrane cadherin receptors.
15.18 Adherens junctions link adjacent
cells
• The best-known adherens junction is
the zonula adherens.
– It is located within the junctional complex
that forms between neighboring epithelial
cells in some tissues.
• Within the zonula adherens, adaptor
proteins called catenins link cadherins
to actin filaments.
15.19 Desmosomes are intermediate
filamentbased cell adhesion complexes
• The principal function of desmosomes is
to:
– provide structural integrity to sheets of
epithelial cells by linking the intermediate
filament networks of cells.
15.19 Desmosomes are intermediate filament-based cell adhesion
complexes
• Desmosomes are components of the
junctional complex.
• At least seven proteins have been
identified in desmosomes.
• The molecular composition of
desmosomes varies in different cell and
tissue types.
15.19 Desmosomes are intermediate filament-based cell adhesion
complexes
• Desmosomes function as both:
– adhesive structures
– signal transducing complexes
• Mutations in desmosomal components
result in fragile epithelial structures.
– These mutations can be lethal, especially if
they affect the organization of the skin.
15.20 Hemidesmosomes attach epithelial
cells to the basal lamina
• Hemidesmosomes, like desmosomes,
provide structural stability to epithelial
sheets.
• Hemidesmosomes are found on the
basal surface of epithelial cells.
– There, they link the extracellular matrix to
the intermediate filament network via
transmembrane receptors.
15.20 Hemidesmosomes attach epithelial cells to the basal
lamina
• Hemidesmosomes are structurally
distinct from desmosomes.
• They contain at least six unique
proteins.
15.20 Hemidesmosomes attach epithelial cells to the basal
lamina
• Mutations in hemidesmosome genes
give rise to diseases similar to those
associated with desmosomal gene
mutations.
• The signaling pathways responsible for
regulating hemidesmosome assembly
are not well understood.
15.21 Gap junctions allow direct transfer
of molecules between adjacent cells
• Gap junctions are protein structures that
facilitate direct transfer of small
molecules between adjacent cells.
• They are found in most animal cells.
15.21 Gap junctions allow direct transfer of molecules between
adjacent cells
• Gap junctions consist of clusters of
cylindrical gap junction channels, which:
– project outward from the plasma
membrane
– span a 2-3 nm gap between adjacent cells
• The gap junction channels consist of
two halves, called connexons or
hemichannels.
– Each consists of six protein subunits called
connexins.
15.21 Gap junctions allow direct transfer of molecules between
adjacent cells
• Over 20 different connexin genes are
found in humans.
– These combine to form a variety of
connexon types.
• Gap junctions:
– allow for free diffusion of molecules 1200
daltons in size
– exclude passage of molecules 2000
daltons
15.21 Gap junctions allow direct transfer of molecules between
adjacent cells
• Gap junction permeability is regulated
by opening and closing of the gap
junction channels, a process called
“gating.”
• Gating is controlled by changes in
– intracellular pH
– calcium ion flux
– direct phosphorylation of connexin subunits
15.21 Gap junctions allow direct transfer of molecules between
adjacent cells
• Two additional families of nonconnexin
gap junction proteins have been
discovered.
– This suggests that gap junctions evolved
more than once in the animal kingdom.
15.22 Calcium-dependent cadherins
mediate adhesion between cells
• Cadherins constitute a family of cell
surface transmembrane receptor
proteins that are organized into eight
groups.
• The best-known group of cadherins is
called the “classical cadherins.”
– It plays a role in establishing and
maintaining cell-cell adhesion complexes
such as the adherens junctions.
15.22 Calcium-dependent cadherins mediate adhesion
between cells
• Classical cadherins function as clusters
of dimers.
• The strength of adhesion is regulated by
varying both:
– the number of dimers expressed on the cell
surface
– the degree of clustering
15.22 Calcium-dependent cadherins mediate adhesion
between cells
• Classical cadherins bind to cytoplasmic
adaptor proteins, called catenins.
– Catenins link cadherins to the actin
cytoskeleton.
• Cadherin clusters regulate intracellular
signaling by forming a cytoskeletal
scaffold.
– This organizes signaling proteins and their
substrates into a three-dimensional
complex.
15.22 Calcium-dependent cadherins mediate adhesion
between cells
• Classical cadherins are essential for
tissue morphogenesis, primarily by
controlling:
– specificity of cell-cell adhesion
– changes in cell shape and movement
15.23 Calcium-independent NCAMs
mediate adhesion between neural cells
• Neural cell adhesion molecules
(NCAMs) are expressed only in neural
cells.
• They function primarily as homotypic
cell-cell adhesion and signaling
receptors.
15.23 Calcium-independent NCAMs mediate adhesion between
neural cells
• Nerve cells express three different types
of NCAM proteins.
– They arise from alternative splicing of a
single NCAM gene.
15.23 Calcium-independent NCAMs mediate adhesion between
neural cells
• Some NCAMs are covalently modified
with long chains of polysialic acid
(PSA).
– This reduces the strength of homotypic
binding.
• This reduced adhesion may be
important in developing neurons as they
form and break contacts with other
neurons.
15.24 Selectins control adhesion of
circulating immune cells
• Selectins are cell-cell adhesion receptors
expressed exclusively on cells in the vascular
system.
• Three forms of selectin have been identified:
– L-selectin
– P-selectin
– E-selectin
15.24 Selectins control adhesion of circulating immune
cells
• Selectins function to arrest circulating
leukocytes in blood vessels so that they
can crawl out into the surrounding
tissue.
• In a process called discontinuous cellcell adhesion, selectins on leukocytes
bind weakly and transiently to
glycoproteins on the endothelial cells.
– The leukocytes come to a “rolling stop”
along the blood vessel wall.