Cell Junctions and Extracellular Matrix Overview

• Cell junctions and the extracellular matrix are the focus of this chapter
• The contents are an overview of cell adhesion, cell-cell junctions, the extracellular matrix and cell-matrix adhesions, and key concepts of mechanotransduction

Fundamental Feature of Multicellular Organisms

• Cell adhesions integrate cells of different lineages into a defined tissue architecture
• Cell adhesions determine the physical properties of tissues like architecture, shape, and elasticity
• Dynamic remodeling of cell adhesions underlies tissue development and repair
• Cell adhesions facilitate the exchange of biochemical and biophysical information between neighboring cells and at a supracellular level
• Genetic defects in adhesion genes can lead to severe diseases
• Mechanical stresses transmit from cell to cell by cytoskeletal filaments anchored to cell-matrix and cell-cell adhesion sites
• The extracellular matrix directly bears mechanical stresses of tension and compression

Types of Adhesion Structures

• Epithelia are structurally polarized
• Different adhesion structures have distinct subcellular distribution
• All adhesion structures connect to the cytoskeleton
• Tight junctions seal the gap between epithelial cells
• Adherens junctions connect actin filament bundles in one cell to the next
• Desmosomes connect intermediate filaments in one cell to those in the next cell
• Gap junctions allow passage of small water-soluble molecules from cell to cell
• Actin-linked cell-matrix junctions anchor actin filaments in cells to the extracellular matrix
• Hemidesmosomes anchor intermediate filaments in a cell to the extracellular matrix

Anchoring Junctions (Table 19-1)

• Adherens junctions involve classical cadherins, interact with classical cadherins on neighboring cells, attach to actin filaments, and use α-Catenin, β-Catenin, plakoglobin (γ-Catenin), p120-catenin, and vinculin as adaptor proteins
• Desmosomes use nonclassical cadherins (desmoglein, desmocollin), interact with desmoglein and desmocollin on neighboring cells, attach to intermediate filaments, and use Plakoglobin (γ-catenin), plakophilin, and desmoplakin as adaptor proteins
• Actin-linked cell-matrix junctions use integrin, interact with extracellular matrix proteins, attach to actin filaments, and use talin, kindlin, vinculin, paxillin, and focal adhesion kinase (FAK) as adaptor proteins
• Hemidesmosomes use α6β4 Integrin, type XVII collagen, interact with extracellular matrix proteins, attach to intermediate filaments, and use plectin and BP230 as adaptor proteins

Key Functions of Cell Adhesions

• Adhesion structures are linked to the cytoskeleton and integrate various cell types, providing mechanical coherence
• Cell adhesion enables cells to sense and respond to mechanical stimuli from their microenvironment
• Dynamic remodeling of cell adhesion enables cell movement, tissue development, and repair

Adherens Junctions

• Cadherins form a diverse family of adhesion molecules with over 180 members in humans
• Adherens junctions are found in all multicellular organisms, but are absent in unicellular organisms
• The junctions are mediated by classical cadherins and are connected to the actin cytoskeleton

Cadherins

• Classical cadherins include E-cadherin, found mostly in epithelial cells, N-cadherin, found on nerve, muscle, and lens cells, and P-cadherin, found on cells in the placenta and epidermis
• Nonclassical cadherins include protocadherins, found in the brain, and desmocollins and desmogleins, which form desmosomes
• Cadherin contains multiple rigid extracellular cadherin (EC) domains
• Structural stability for cadherins requires calcium at the hinge region
• Cadherins mediate homophilic adhesion to create a symmetrical structure between neighboring cells
• Homophilic binding occurs at the distal EC domain
• Spacing between cell membranes at the adhesion junction is defined by the length of cadherin
• Weak monovalent binding affinity is compensated by cadherin clustering for high avidity
• Homophilic cadherin interactions are highly specific
• Cell type-specific expression mediates homotypic cell-cell adhesion
• Self-organization of multiple cell types can occur in tissue

Mechanical Sensitivity of Adherens Junctions

• Catenins link classical cadherins to the actin cytoskeleton
• Adherens junctions respond to forces generated by the actin cytoskeleton
• Force induces adhesion strengthening
• A mechanical balance is achieved between neighboring cells
• Cell protrusions initiate contact, then actin protrusions expand adherens junctions, and then contractile actin bundles support the AJs

Actin-Myosin Bundles

• Actin-myosin bundles are integrated into a transcellular network
• Adhesion belts, also known as zonula adhesion, contains actin filaments, cadherins, and tight junctions
• Invagination of an epithelial sheet is caused by organized tightening of adhesion belts in select regions of the cell sheet
• Epithelial tubes pinch off from overlying sheets of cells through this process

Tissue Remodeling

• Tissue remodeling relies on the coordination of actin-mediated contraction with cell-cell adhesion
• Germ-band extension of the outer epithelium happens in the development of Drosophila embryos
• Cadherin-mediated adhesion coordinates collective migration in epithelial wound healing

Epithelial-Mesenchymal Transition (EMT)

• During EMT, epithelial cells transition from an epithelial state to a mesenchymal state
• The epithelial state is marked by E-cadherin, epithelial cell adhesion molecules, occludins, claudins, α6β4 integrins, and cytokeratins
• The mesenchymal state is marked by N-cadherin, vimentin, fibronectin, β1 and β3 integrins, and MMPs
• ZEB family, SNAIL or SLUG, and TWIST1 proteins repress the epithelial state and induce the mesenchymal state
• During MET, mesenchymal cells undergo changes in their gene expression and protein production that cause them to revert back to an epithelial state
• EMT can happen during cancer metastasis

Desmosomes

• Desmosomes contain specialized nonclassical cadherins and link to intermediate filaments, providing epithelia with mechanical strength
• Keratin is present in epithelia, while desmin is present in cardiac muscle
• Desmosomes link a transcellular network of intermediate filaments
• Mutations in desmosome components can lead to diseases
• Epidermolysis bullosa simplex is a characterized by mutations in keratin 5 or 14 that affect the skin
• Lethal acantholytic epidermolysis bullosa can be caused by mutations in desmoplakin

Tight Junctions

• All epithelia are selective permeability barriers
• Tight junctions establish an epithelial barrier function, limiting free diffusion of molecules across the epithelium, and they separate apical membrane from the basolateral membrane, limiting membrane protein diffusion between membrane domains.
• They are impermeable to macromolecules, but permeability to ions and other small molecules varies across tissues
• Claudin and occludin form tight junctions, which have transmembrane adhesion proteins
• 24 claudin family proteins in humans allows for different combinations that confer tissue-specific selective permeability
• Claudin-based tight junctions are crucial for the mammalian epidermal barrier, as evidenced by claudin-1-deficient mice

Gap Junctions

• Gap junctions couple cells electrically and metabolically and are made of connexin channels; there are 21 isoforms in humans
• Gap junctions exhibit cell-type specificity and can be heteromeric and heterotypic
• Gap junctions appear as a patch where the membranes of two adjacent cells are separated by a uniform gap of about 2–4 nm when viewed under conventional electron micrographs
• These are made of connexins and connexons between intercellular channels
• A gap junction connexon is a hemichannel made of six transmembrane connexin subunits
• Gap junctions have dynamic turnover
• The 1.4nm pore diameter allows exchange of inorganic ions and other small molecules, but not macromolecules such as proteins or nucleic acids
• Electrical coupling via gap junctions makes them critical in the heart
• Leaky connexin 26 hemichannels lead to Keratitis Ichthyosis Deafness (KID) syndrome that present with keratitis, keratoderma, and sensorineural deafness
• Cells can communicate biochemical signals via gap junctions

Selectins

• Selectins are calcium-dependent (C-type) glycan-binding lectins
• They mediate leukocyte transient cell-cell adhesions in the bloodstream: L-selectin on leukocytes, P-selectin on endothelial cells and activated platelets, and E-selectin on activated endothelial cells
• Selectin-glycan interactions initiate recruitment of leukocytes to inflamed tissues
• Leukocyte adhesion deficiency-type 2 can be caused by a loss of selectin binding on PSGL1

Immunoglobulin (Ig) Family Adhesion Molecules

• ICAMs (intercellular cell adhesion molecules)
• VCAMS (vascular cell adhesion molecules)
• NCAM (neural cell adhesion molecule)

Summary

• Cell adhesion is a hallmark for multicellular organisms, integrating different cell types into a coherent entity
• Cell adhesions determine the physical properties of tissues like architecture, shape, and elasticity
• Dynamic remodeling of cell adhesions underlies tissue development and repair
• Cell adhesions allow exchange of biochemical and biophysical information between neighboring cells and on a supracellular level
• Cell-cell adhesion comprises adherens junctions, tight junctions, desmosomes, and gap junctions
• Other types cell adhesions include selectins and immunoglobulin (Ig) family adhesion molecules
• Mutations or dysregulation of adhesion molecules lead to severe diseases, including cancer metastasis (EMT), epidermolysis bullosa (keratin 5/14, desmoplakin), Keratitis ichthyosis deafness syndrome (connexin 26), and leukocyte adhesion deficiency-type 2 (loss of selectin binding on PSGL1)

Overview of cell adhesion, cell-cell junctions, and the extracellular matrix. Explore cell-matrix adhesions and the vital concept of mechanotransduction. Integrates cells into tissue, determines tissue properties, and aids tissue repair.