Transcript MB207_17 - MB207Jan2010

MB 207 Molecular cell biology
Cell junctions, cell adhesion
and the extracellular matrix
Cell junctions, cell adhesion and the
extracellular matrix
• Cell Junctions
¤ Occluding junctions
¤ Anchoring junctions
¤ Communicating junctions
• Cell adhesion molecules
¤ Cadherins
¤ Selectins
¤ Integrins
¤ Immunoglobulin superfamily
• Extracellular matrix
• In muticellular organisms, individual cells are organized into tissues
that allows multicellular organisms to adopt complex structures.
→ Cells must be attached to one another.
• In order for individual cells to associate in precise patterns to form
tissues, organs and organ systems, individual cells must be able to
recognize, adhere to and communicate with each other.
•
These associations usually involve specialized modifications of the
plasma membrane at the point where two cells come together.
→ cell junctions
• In addition, cells also interact with extracellular materials that are
crucial for tissue structure and fucntion.
→ extracellular matrix
Cell Junctions
•
Occurs at points of cell-cell and cell-matrix contact in all tissues.
•
Categorized into three functional groups:
-- Occluding junctions: seal cells together to prevent even
small molecules from leaking from one side of the cell to the
other, e.g. tight junctions.
– Anchoring junctions: mechanically attach cells to their
neighbours or to the extracellular matrix, e.g. adherens
junctions, focal junctions, desmosomes & hemidesmosomes.
– Communicating junctions: mediate the passage of a
chemical or electrical signals from one interacting cell to its
partner, e.g. gap junctions.
Occluding junctions
– Role carried by tight junctions (vertebrate).
– Functions:
i) Maintenance of selective permeability,
separating fluids on either side that have a
different chemical composition.
ii) Seal neighboring cells together.
– Confine the transport proteins to their
appropriate membrane domain by acting as
diffusion barriers.
– Can be regulated to permit increase flow of
solutes or water at the barriers
→ paracellular transport (amino acids and
monosaccharides).
– Structure:
Composed of a branching network of sealing
strands that completely encircles the apical end
of each cell.
→ Each tight junction sealing strand is
composed of a long row of transmembrane
adhesion proteins (e.g. claudins & occludin)
embedded in each of the 2 interacting plasma
membranes.
Anchoring junctions
• Link cells together into tissues, thereby enabling
the cells to function as a unit
→ Anchoring cytoskeleton to the cell surface.
→ Resulting interconnected cytoskeletal network
helps to maintain tissue integrity and to withstand
mechanical stress.
• Composed of two main classes of proteins:
i) intracellular anchor proteins
→ link the junction to the appropriate
cytoskeletal filaments on the cytoplasmic face of
the plasma membrane.
ii) transmembrane adhesion proteins
→ cytoplasmic tail that binds to one or more
intracellular anchor proteins and an extracellular
domain that interacts with either extracellular
matrix or extracellular domains of a specific
transmembrane adhesion proteins on another cell.
• Occurs in two functionally different forms:
i) Adherens junctions and desmosomes hold cells together and
formed by transmembrane adhesion proteins that belong to the
cadherin family.
ii) Focal adhesions and hemidesmosomes bind cells to the
extracellular matrix and are formed by transmembrane adhesion
proteins of the integrin family.
Junction
Transmembrane
proteins
Extracellular Ligand
Intracellular cytoskeletal
attachment
Adherens junction
Cadherin (Ecadherin)
Cadherin in neighbouring
cell
Actin filaments
Desmosome
Cadherin
(desmoglein,
desmocollin)
Desmoglein &
desmocollin in
neighbouring cell
Intermediate filaments
Focal adhesion
Integrin
ECM
Actin filaments
Hemidesmosome
Integrin
ECM
Intermediate filaments
Adherens junctions
•
•
•
Connect the actin of a cell to the actin of its neighbours.
Prominent in epithelial cells.
Structure:
→ forms a continuous belt that encircles the cell near the apical end of the
lateral membrane.
Desmosomes
•
•
Connect the intermediate filaments of a cell to the intermediate filaments
of its neighbors.
Structure:
¤ Button-like points of strong adhesion between adjacent cells in a tissue.
→ serves as an anchoring sites for intermediate filaments, which form a
structural framework of great tensile strength.
Focal adhesions
•
•
Connect actin of a cell to the extracellular matrix through integrins.
The extracellular domains of transmembrane integrin proteins bind to a
protein component of the extracellular matrix, while their intracellular
domains bind indirectly to bundles of actin filaments via intracellular
anchor proteins.
Hemidesmosome
•
•
Connecting intermediate filaments of a cell to extracellular matrix
Extracellular domains of integrins mediate the adhesion bind to a laminin
protein in the basal lamina, while an intracellular domains binds via an
anchor protein to keratin intermediate filaments.
Communicating junctions: Gap junctions
• Region where the plasma membranes of two cells
are aligned and brought into intimate contact.
→ uniform narrow gap which is spanned by
channel-forming proteins (connexins).
• The gap is spanned by channel-forming proteins
(connexins, 6 subunits), and the pore is called
connexon.
• Permeability of gap junctions in different cells can
vary  different forms of connexins (construction
of transmembrane proteins).
• Individual gap junction channels do not remain
continuously open. They flip between open and
closed states.
• The channels allow inorganic ions and other small
water soluble molecules to pass directly from the
cytoplasm of one cell to the cytoplasm of the other.
→ solutes with molecular weights up to about
1000 daltons.
Summary of cell junctions found in vertebrate
epithelial cell
Cell Adhesion Molecule (CAMs)
• Are cell-surface proteins.
→ adhering cells to each other and to the extracellular matrix.
• Two types:
i) cell-cell adhesion molecules
ii) cell-matirx adhesion molecules
• Three mechanisms by which cell-surface molecules can mediate
cell-cell adhesion:
i) Homophilic binding
ii) Heterophilic binding
iii) Binding through an extracellular linker molecule
Types of CAMs
Cadherins
• Major CAMs responsible for Ca2+-dependent cell-cell adhesion.
• Three types of cadherins: E-cadherin, N-cadherin and P-cadherin.
• Important in initial attachment such as in development of
cells, and maintaining the structure and integrity of cells
• Single-pass transmembrane glycoproteins which normally
function as a dimer/oligomer.
• Linked to actin/intermediate filaments through intracellular anchor
protein.
The linkage of classical cadherins to actin filaments
• The cadherins are coupled indirectly to actin filaments by the anchor protein α-catenin
and β-catenin.
• A third intracellular protein, p120, also binds to cadherin cytoplasmic tail and regulates
cadherin function.
Selectins
• Cell-surface carbohydrate-binding proteins (lectin) that mediate
Ca2+-dependent cell-cell adhesion in the bloodstream.
• 3 types:
¤ L-selectin: on white blood cells
¤ P-selectin: on platelets and some endothelial cells
¤ E-selectin: on activated endothelial cells
• Transmembrane protein with highly conserved lectin domain that
binds to a specific oligosaccharide on another cell.
Integrins
• Main function: Binds and mechanically fixes cells to
ECM.
• Additional functions:
i) serves as cell-cell adhesion molecule.
ii) serves in signal transduction.
• Composed of two noncovalently associated
transmembrane glycoprotein subunits, α and β.
• Divalent ions dependent (Ca2+ or Mg2+)
→ Influence both affinity and specificity of the
binding of an integrin to its ligands.
The regulation of the extracellular binding activity of a cell’s
integrins from within
• An extracellular signal activates an intracellular signaling cascade that alters
the integrin so that its extracellular binding site can now mediate cell adhesion.
Immunoglobulin (Ig) superfamily
• Ca2+-independent cell-cell
adhesion
• Contain 1 or more Ig-like
domains.
• e.g. N-CAM (neural CAM)
• Involve in fine-tuning the
adhesive interaction mediated
by cadherins during
development and regeneration.
Summary of junctional and non-junctional adhesive mechanisms
used by animal cells in binding to one another and to the
extracellular matrix
Cell Adhesion Molecules
Family
Selectins
Integrins
Ig superfamily
Cadherins
Ligands
recognized
Carbohydrates
Stable cell
junctions
No
Extracellular
matrix
Focal adhesions
and
hemidesmosomes
Integrins
Homophilic
interactions
Homophilic
interaction
No
No
Adherens
junctions and
desmosomes
Extracellular Matrix (ECM)
• Tissues are not made up solely of cells.
• Large part of the tissue is extracellular space which is filled by
intricate network of macromolecules constituting the ECM.
• ECM is composed of proteins and polysaccharides that are secreted
locally and assembled into an organized meshwork in close
association with the surface of the cell that produced them.
• Cell surface receptors bind to the extracelular matrix and anchor the
cytoskeleton at cell matrix junction.
• Variation in the types of matrix molecules lead to various different
form of functional connective tissue i.e. bone, teeth, cornea, tendons
etc.