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Anchoring Junctions

• Anchoring junctions can be subclassified according to the cytoskeletal element that is involved.
• There are two types of anchoring junctions:
  • Actin filament attachment sites
  • Intermediate filament attachment sites

Actin Filament Attachment Sites

• Cell-cell junction (ADHERENS JUNCTIONS)
• Cell-matrix junctions (FOCAL ADHESIONS)

Intermediate Filament Attachment Sites

• Cell-cell junctions (DESMOSOMES)
• Cell-matrix junctions (HEMIDESMOSOMES)

Desmosomes

• Strongest points of cell adhesion that provide mechanical binding
• Most abundant in tissues that are exposed to mechanical stress (epidermis of the skin, heart muscle)
• Cell-to-cell binding depends on cadherin family of proteins called desmoglein and desmocollin
• Desmosomes contain plaque-shaped structures on the cytoplasmic face of the junction, which provide attachment sites for intermediate filaments
• Plaque proteins are plakoglobins, desmoplakins, and plakophilins
• Two types of cadherins (desmoglein and desmocollin) link adjacent cells together, and cytoplasmic plaque (desmoplakin, plakoglobin, and plakophilin) links the cadherins
• Desmosomes give tissues mechanical strength
• Desmosomes are found in many tissues, especially abundant in skin (epidermis), heart muscle, and the neck of the uterus

Importance of Desmosome Junctions

• Demonstrated by some of the skin autoimmune diseases, such as PEMPHIGUS
• Affected individuals make antibodies against their own desmosomal cadherins, which bind to and disrupt the desmosomes that hold their skin epithelial cells together

Hemidesmosomes

• Resemble desmosomes morphologically
• Cell uses hemidesmosomes to attach to the basal lamina
• Cell-to-matrix adhesion proteins, such as INTEGRINS, are involved in hemidesmosomes
• Hemidesmosomes have only a single dense plaque on the cytoplasmic surface of the hemidesmosome (hemi=half) that anchors loops of intermediate filaments
• Schematic model of hemidesmosome connecting an epithelial cell to the basal lamina
• Extracellular domains of the integrins bind to laminin protein in the basal lamina, and an intracellular domain binds to an anchor protein (plectin) that binds to keratin intermediate filaments

Hemidesmosome-Related Diseases

• In a blistering skin disease called bullous pemphigoid, autoantibodies attack type XVII collagen
• Mutations in plectin cause skin blisters associated with late-onset muscular dystrophy

Focal Adhesions

• Bind the cells to the extracellular matrix
• Cell-to-matrix adhesion proteins, such as INTEGRINS, are responsible for the binding to the matrix
• Cytoplasmic domain of the integrin binds indirectly to actin filaments
• Integrin's extracellular domains bind to components of the extracellular matrix, while the cytoplasmic tail of the β subunit binds indirectly to actin

Microvillus Structure

• A bundle of parallel actin filaments extend 0.5μ down into the apical cytoplasm and enter into the terminal web
• Actin filaments are cross-linked into closely packed bundles by actin-bundling proteins, villin, and fimbrin, forming the core of a microvillus
• Actin filaments are attached to the plasma membrane by lateral arms consisting of myosin I and calmodulin
• Glycocalix is thicker around the microvilli, forming a striated border, and is PAS+

Cilia and Flagella

• Cilia are eyelash or hair-like processes from the cell surface, motile, and longer than microvilli (5-10μ long, 0.2μ in diameter)
• Under the electron microscope, they have a complex internal structure composed of microtubules
• 250 or more cilia are found in each cell, arranged in parallel rows, and function to move fluid over the surface of the cell
• Found in epithelial cells of the upper respiratory tract, uterine tubes (oviducts), and efferent ducts (Ductus efferentes)

Basal Body Structure

• At the base of a cilium, a central pair of single microtubules terminates
• Each of the peripheral doublets is continuous with a triplet microtubule of the basal body
• Three microtubules are fused together and form a triplet microtubule
• Basal body resembles a centriole but contains some accessory structures such as basal foot and rootlet

Cilia Function

• Ciliary movement is important during development
• Dynein arms are absent from cilia in patients with Kartagener's Syndrome
• Nodal Cilia cannot move during development, and internal organs cannot be located at their normal positions
• Helical beating of cilia at the node, and the origins of left-right asymmetry

Flagella Structure and Function

• Flagellum propels sperm, is longer than cilia (100-200 μ), and has the same internal structure as cilia (Axoneme 9+2)
• Has a different type of movement (undulating wave type of movement) and is less in number (one or two in a single cell)
• Mammalian spermium contains 9 additional dense fibers around the axoneme (9+9+2), which serves a protective function

Microtubule Structure

• Microtubules are hollow tube-like or pipe-like structures
• The wall of the microtubule is composed of 13 protofilaments
• Protofilaments are composed of Tubulin subunits (dimer), which consist of Tubulin α and Tubulin β

Gap Junctions

• Site of firm adhesion of cells
• Allow free interchange of substances
• Important role in regulation of intrauterine development and differentiation
• Coordinate function among groups of cells

Anchoring Junctions

• Two types: Hemidesmosomes and Focal Adhesions

Hemidesmosomes

• Have a single dense plaque on the cytoplasmic surface
• Anchor loops of intermediate filaments
• Integrins bind to laminin protein in the basal lamina
• Intracellular domain binds to an anchor protein (plectin) that binds to keratin intermediate filaments
• Found in epithelial cells, attach to basal lamina
• Mutations in plectin cause skin blisters
• Autoantibodies attack type XVII collagen in bullous pemphigoid, a blistering skin disease

Focal Adhesions

• Bind cells to the extracellular matrix
• Cell-matrix adhesion proteins; integrins responsible for binding to the matrix
• Cytoplasmic domain of the integrin binds indirectly to actin filaments
• Integrin's extracellular domains bind to components of extracellular matrix
• Cytoplasmic tail of the β subunit binds indirectly to actin

Adhesion Proteins

• Fibrin: a major ECM component of blood clots
• Forms an elastic network to which cells and other ECM components bind
• Polymerization of fibrin to form the network occurs when its precursor molecule fibrinogen is cleaved by the enzyme thrombin
• Fibrin has binding interactions with various extracellular components, including fibronectin, heparin, growth factors, and cytokines
• Fibrinolysis is mediated by plasmin, which cleaves fibrin

Von Willebrand Factor

• Plays a key role in the major response of platelets to vascular injury by mediating the initiation and progression of thrombus formation
• Enables cell adhesion to develop by forming a bridge between collagen in the vessel wall and blood platelets

Desmosomes

• Strongest points of cell adhesion that provide mechanical binding
• Most abundant in tissues that are exposed to mechanical stress (epidermis of the skin, heart muscle)
• Cell-to-cell binding depends on cadherin family of proteins called desmoglein and desmocollin
• Contain plaque-shaped structures on the cytoplasmic face of the junction which provide attachment sites for intermediate filaments
• Plaque proteins are plakoglobins, desmoplakins, and plakophilins
• Found in many tissues, especially abundant in skin, heart muscle, and the neck of the uterus
• Importance of desmosome junctions is demonstrated by some skin autoimmune diseases, such as pemphigus, where affected individuals make antibodies against their own desmosomal cadherins

Desmosomes

• Strongest points of cell adhesion that provide mechanical binding
• Most abundant in tissues exposed to mechanical stress (epidermis of the skin, heart muscle)
• Contain plaque-shaped structures on the cytoplasmic face of the junction, providing attachment sites for intermediate filaments
• Plaque proteins include plakoglobins, desmoplakins, and plakophilins
• Two types of cadherins (desmoglein and desmocollin) link adjacent cells together
• Cytoplasmic plaque (desmoplakin, plakoglobin, and plakophilin) links the cadherins to intermediate filaments

Importance of Desmosomes

• Desmosomal cadherins are targeted in autoimmune diseases such as Pemphigus, leading to blistering of the skin
• Affected individuals make antibodies against their own desmosomal cadherins, disrupting desmosomes and causing skin epithelial cells to separate

Intermediate Filaments

• Types of intermediate filaments include keratin filaments in epithelial cells and desmin filaments in heart and muscle cells
• Intermediate filaments can be subclassified according to the cytoskeletal element involved

Anchoring Junctions

• Subclassified into two types:
  • Intermediate filament attachment sites
    • Cell-cell junctions (desmosomes)
    • Cell-matrix junctions (hemidesmosomes)
  • Actin filament attachment sites
    • Cell-cell junctions (adherens junctions)
    • Cell-matrix junctions (focal adhesions)

Hemidesmosomes

• Resemble desmosomes morphologically
• Cell uses hemidesmosomes to attach to the basal lamina
• Contain a single dense plaque on the cytoplasmic surface that anchors loops of intermediate filaments
• Schematic model shows an epithelial cell attached to the basal lamina via hemidesmosomes
• Autoantibodies attack type XVII collagen in bullous pemphigoid, a blistering skin disease
• Mutations in plectin cause skin blisters associated with late-onset muscular dystrophy

Adherens Junctions

• Actin filament bundles are attached by intracellular anchor proteins to cadherins
• Cadherins are transmembrane proteins that bind to those of adjacent cells, tying actin filament bundles together
• Adherens junctions in the form of adhesion belts between epithelial cells in the small intestine
• Role in early development: controlled contraction of actin filament bundles causes epithelial cells to narrow and form a tube in vertebrate development

Anchoring Junctions

• Anchoring junctions can be subclassified according to the cytoskeletal element involved
• Two types of anchoring junctions:
  • Actin filament attachment sites
    • Cell-cell junctions (ADHERENS JUNCTIONS)
    • Cell-matrix junctions (FOCAL ADHESIONS)
  • Intermediate filament attachment sites
    • Cell-cell junctions (DESMOSOMES)
    • Cell-matrix junctions (HEMIDESMOSOMES)

Desmosomes

• Desmosomes are strongest points of cell adhesion that provide mechanical binding
• Most abundant in tissues that are exposed to mechanical stress (Epidermis of the skin, heart muscle)
• Cell to cell binding depends on cadherin family of proteins called desmoglein and desmocollin
• Desmosomes contain plaque-shaped structures on the cytoplasmic face of the junction which provide attachment sites for intermediate filaments
• Plaque proteins: plakoglobins, desmoplakins, plakophilins

Hemidesmosomes

• Hemidesmosomes resemble desmosomes morphologically
• Hemidesmosomes have only a single dense plaque on the cytoplasmic surface of the hemidesmosome (hemi=half) that anchors loops of intermediate filaments
• Hemidesmosomes connect epithelial cells to the basal lamina
• Integrin (α6β4) and type XVII collagen (also called BPAG2) attach to the basal lamina

Importance of Desmosomes and Hemidesmosomes

• In a blistering skin disease called bullous pemphigoid, autoantibodies attack type XVII collagen
• Mutations in plectin cause skin blisters associated with late-onset muscular dystrophy
• Cataract, heart malformations, and skin blistering are examples of diseases related to desmosome and hemidesmosome dysfunction