Cell-to-Cell and Cell-to-Matrix Adhesions

Test Your Knowledge:

1. Where would you find the basal lamina? Proteoglycans? Fibronectin?

2. Name one type of cell-to-cell connection.

3. Name one type of cell to extracellular matrix connection

4. Name one type of cell membrane to cytoskeleton connection.

5. Name one function of the extracellular matrix

6. True/False Specific extracellular matrix components can directly activate cytosolic signal transduction pathways.

Cells combine to form tissues. This requires that cells “adhere” to one another to form a functional unit.

Types of adhesion:

• Cell-to-cell adhesion

• Cell-to-extracellular matrix adhesion;

Types of interactions between adhesion proteins:

• Homophilic – adhesion created by interaction between two similar adhesion molecules

• Heterophilic – adhesion created by interaction between two different adhesion molecules or between adhesion molecules and cytoskeleton or extracellular matrix proteins

• Homotypic – adhesion between similar molecules

• Heterotypic – adhesion between different molecules

5 classes of CAMs

Not shown: mucins

Cell-to-cell adhesion molecules

1. Calcium dependent adhesion molecules (cadherins)• Evolutionarily ancient; widely expressed; over 12 different types known

• Almost all vertebrate cells express one or more

Structure: Single-pass transmembrane glycoprotein composed of about 700-750 residues

Type of binding:

Types:

•Interactive with actin cytoskeleton: Cadherins N; P; R; B; E

•Desmosome associated: Desmogleins & Desmocollins

•Protocadherins

Location:

E-Cadherin Domains 1 and 2 In Complex With Calcium

Two of the 5 tandem repeats of extracelluar region

2. Non calcium dependent adhesion molecules

(NCAMs nerve cell adhesion molecules, ICAMs, and L1)

• Evolutionarily ancient; widely expressed

• Belong to the immunoglobulin (Ig) superfamily

Structure: single pass, transmembrane proteins which may bind to the cytoskeleton inside cells

Type of adhesion:

Can have both homophilic and heterophilic interactions;

homo – neural specific Ig Cell Adhesion molecules (IgCAMs);

hetero systemic IgCAMs

Functions:

neurite outgrowth, myelination, and

firm adhesion of leukocytes

3. Selectins

• Expressed only in vertebrates; in circulatory cells (endothelium and blood cells)

• Transient transmembrane binding proteins (lectins)

• In the presence of calcium, bind to specific oligosaccharides on another cell

Structure: single transmembrane polypeptide

Type of adhesion:

Function:

extravasation

Cell to extracellular matrix adhesion molecules

1) Integrins (examples: laminin, fibronectin, fibrinogen)

• A family of transmembrane adhesion molecules (usually glycoproteins) that exist in variable activation states

• Extracellular matrix receptors on integrins have selective affinity for certain matrix proteins; allows cells to explore their environment

Structure: have an alpha and a beta subunit (heterodimer); alternative splicing has led to 16 different chains and 8 different chains

Type of adhesion:

Function: WBC binding to endothelium;

Epithelial tissues – what do they need adhesion molecules for?tight junctionsadherens junctionsdesmosomehemidesmosome

Tight Junctions

Function:

Protein composition:

occludin

claudin

junction adhesion molecules (JAMs)

Cytosolic face

Adherens junctions (adhesion belt); attach to actin

Desmosomes; attach to intermediate filaments

Focal adhesions

Hemidesmosomes

Adherens Junctions

Composition: cadherens

Function: can contract (with help of myosin)

Folding of sheets into tubes during morphogenesis, other folding processes during morphogenesis

Binding partners:

catenins, and via catenins to cytoskeleton (actin)

desmosomepemphigus

Focal Adhesions

Examples: myotendinous junction

fibroblast migration in connective tissue

Basal Lamina – extracellular matrix; a sheetlike meshwork underlying or surrounding groups of cells

Function :

Components of the basal lamina; produced by cells that rest on it (mainly fibroblasts); sometimes called the basement membrane

• Type IV collagen

• Laminins

• Entactin (nidogen and laminin)

• Perlecan

The regulatory factors which impact on matrix synthesis, degradation and function are many and include 'growth factors', cytokines, hormones, vitamins, matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs).

Vitamins: C, D

Hormones: estrogens, glucocorticoids,

Matrix Metalloproteinases MMP: zinc containing enzymes that degrade most molecules of the ECM

Tissue Inhibitors of Metalloproteinases TIMP: zinc binding endopeptidases

Growth Factors: TGFß promotes cellular movement through matrix, and is involved in imflammation and repair

Proteoglycans – glycoproteins containing covalently linked polysaccharide chains called glycosaminoglycans (GAGs); high viscosity and low compressibility

hyaluronanAlso: chondroitin or dermatan sulfate, keratan sulfate, heparan sulfate/heparin-

Common structural make-up of GAGs attachment to proteins; proteoglycans or mucopolysaccharides

95% carbohydrate by weight

Possible functions:

• Selective sieve; regulate movement of molecules and cells

• Chemical signaling between cells; bind certain growth factors (FGF) to stimulate proliferation in the area; TGF binds to several core proteins of the proteoglycan group

• Bind and regulate proteases and protease inhibitors (may restrict range of action, sterically block activity, provide a reservoir for later release, prolong action, or alter concentration)

GAG Localization Comments

Hyaluronatesynovial fluid, vitreous humor,

ECM of loose connective tissue

large polymers, shock absorbing

Chondroitin sulfate

cartilage, bone, heart valves most abundant GAG

Heparan sulfate

basement membranes,components of cell surfaces

contains higher acetylated

glucosamine than heparin

Heparin

component of intracellular granules of mast cells

lining the arteries of the lungs, liver and skin

more sulfated than heparan sulfates

Dermatan sulfate

skin, blood vessels, heart valves

Keratan sulfate

cornea, bone, cartilage aggregated with

chondroitin sulfates

ECM proteins in connective tissue

• Collagen

• Proteoglycans

• Adhesion proteins

• Hyaluronan

• Elastic fibers

Tendon – dense connective tissue

Type IV collagen

• Repeating sequence (Glycine – X –Y)n X = proline Y= hydroxyproline

• Left handed helix. N-terminal and C-terminal ends have globular domains (solubility; cleaved when secreted from cell - insoluble)

• In ER and Golgi they are glycosylated, OH groups added, S-S links three chains

• End result a triple helix

Different types of collagen can co-assemble to form large fibers. Type VI +type I in tendons, form in direction of stress. Type II and Type IX oriented randomly and are in cartilage for strength and compressibility.

Perlecan

Laminins – multiadhesive matrix proteins

Function: organization of basement membrane; have binding sites for itegrin receptors (important in embryonic development and tissue remodeling)

•Laminins are tightly associated with entactin or nidogen a 150-kD sulfated glycoprotein, which also binds to type IV collagen. As a result of these multiple interactions, laminin, entactin, type IV collagen, and perlacan form crosslinked networks in the basal lamina.

Cartilage proteoglycan aggregate

Adhesions between non-epithelial, cells and the extracellular matrix – short and long term adhesions that help in motility

• Focal adhesions

• Focal contacts

• Focal complexes,

• 3D adhesions

• Fibrillar adhesions

• Podosomes

Two conformations of integrins

Change in conformation transferred to other proteins scaffolded to internal signaling pathways