Transcript ch7 FA 11 - Cal State LA

The Extracellular Space
• Epithelial tissues
– closely packed cells lining spaces in the body (e.g. skin, intestine, etc)
• Connective tissues
– Largely composed of non-living extracellular material (e.g. cartilage, tendon, dermis)
The Extracellular Space
• Proteins in plasma membrane have sugars attached
• Glycocalyx
–
–
–
–
Mediate cell interactions
Provide mechanical support
Barrier to particles
Binding sites for regulatory factors
The Extracellular Matrix (ECM)
• An organized network of materials located beyond the plasma membrane
The Extracellular Matrix (ECM)
• Basement membranes
– Thick regions of ECM
• Surround muscle/fat
• Underlie the basal surface of epithelial tissues
The Extracellular Matrix (ECM)
• Basement membranes
– Separate different tissues
– Provide mechanical support
– Barrier to macromolecule and cellular movement
– Substrate for cell migration
– Generate signals that maintain cell survival
The Extracellular Matrix (ECM)
• Collagens (27 different types)
– High tensile strength (resistant to pulling forces)
– Alpha-helical trimers bundle together into fibrils
– Types I, II, III (fibrillar) form rigid cables
• Adjacent collagens are strengthened by covalent cross-links
– Hydroxylysine - lysine
– Type IV (nonfibrillar) can form an interconnected lattice
The Extracellular Matrix (ECM)
• Collagens (27 different types)
– Type IV (nonfibrillar) can form an interconnected lattice
• Composed of helical and non-helical segments (flexibility)
• Globular domains at each end (lattice contact points)
– Collagens bind:
• Fibronectins
• Integrins (cell surface)
The Extracellular Matrix (ECM)
• Diseases caused by defects in collagen genes
– Osteogenesis imperfecta
• Fragile bones
– Ehlers-Danlos syndrome
• Hyperflexible joints, highly extensible skin
The Extracellular Matrix (ECM)
• Proteoglycans
– Protein core + glycosaminoglycan (GAG) polysaccharide complex
• Chondroitin sulfate & keratin sulfate
• High amount of negative charge binds cations and H2O
• Hydrated gel resists compressive forces
– Hyaluronic acid links many proteoglycans to form extremely large molecules
– Fill the scaffold created by collagens
The Extracellular Matrix (ECM)
• Fibronectins
– Modular domains for interactions
– Bind collagens, proteoglycans, integrins at cell surface
– Important for:
• linking ECM components together, cell attachment to matrix, cell migration
NC cells
The Extracellular Matrix (ECM)
• Laminins
– 3 polypeptides linked by disulfide bonds
– Form a second lattice interwoven with Collagen
IV lattice
– Bind to proteoglycans, integrins at cell surface
PGC on laminin
ECM Remodeling
• Matrix metalloproteinases (MMPs)
– Enzymes that degrade ECM proteins
– Tissue remodeling
– Cell migration
– Wound healing
Steps leading to metastatic spread
MMP activity
Cell - ECM Interactions
• Integrins
– Only found in animals
– Heterodimer of alpha and beta subunits
• 18 alpha and 8 beta subunits known
• 12 different alpha/beta combinations known
– Transmembrane proteins
• Extracellular domain, transmembrane domain, intracellular domain
• Inside-out signaling
– Post-translational alterations to cytoplasmic tail regulate conformation
changes in extracellular domain
– Talin separates beta from alpha to open receptor to active state
Plasma membrane
talin
Inactive
Active
Cell - ECM Interactions
• Ligand binding
– RGD loop of Fibronectin binds to integrin
receptor extracellular domain
– Isolated RGD Loop can be exploited to
block platelet aggregation / blood clotting
Cell - ECM Interactions
• Integrins
– Two major functions
• Adhesion to substrate
– Receptors cluster
increasing overall
strength
• Signal transmission
– Binding of ligand
(collagen) can
change cytoplasmic
domain
– Cytoplasmic
domain can activate
kinases such as
FAK and Src
– Activated kinases
can transmit signals
to nucleus and
change gene
expression
Cell - ECM Interactions
• Structures important for adhesion to substrate
– Focal adhesions:
• Scattered, discrete, transient, dynamic, rapidly form and break
• Clusters of integrins bound to collagen / Fibronectin
• Cytoplasmic domains attach to cytoskeleton connecting exterior forces to
internal signals
– Actin filaments
– Focal adhesion kinase (FAK)
Forces exerted by focal adhesions
Cell - ECM Interactions
• Structures important for adhesion to substrate
– Hemidesmosome
• more permanent anchor to basement membrane
• Integrins bound to laminin to dense collection of intermediate filaments
Cell - ECM Interactions
• Structures important for adhesion to substrate
– Hemidesmosome
• Disease: epidermolysis bullosa
– Epidermis poorly connected to basement membrane / dermis
– Fluid accumulates in between = blister
Epidermolysis
Bullosa Type Genes Mutated
Simplex
Junctional
Dystrophic
Keratin-5; Keratin-14; plectin
laminin-5; collagen XVII; a6b4 integrin
collagen VII
(keratins)
Cell - ECM Interactions
Cell - Cell Interactions
• Cadherins: Ca2+ dependent adhesion
– Homophilic interactions allow self-sorting of mixed cell populations
– Disease role: metastasis of cancer
• Lose adhesion by downregulating cadherin expression
• Penetrate / invade barriers by upregulating MMP expression
Cell - Cell Interactions
• Structures important for cell-cell adhesion
– Adherens junctions (30nm gap between cells)
• Cadherin-cadherin interactions in belt-like strips holding two cells together
• Cytoplasmic domains link via beta-catenin and alpha-catenin to the cytoskeleton
Cell - Cell Interactions
• Structures important for cell-cell adhesion
– Desmosomes (1 um diameter disc)
• Resist mechanical stress
• Cadherin-cadherin interactions linked to cytoskeleton (intermediate filaments)
Cell - Cell Interactions
• Tight junctions
– Seal two membranes together
– Block paracellular movement
– Occludin and claudins (24 genes)
– Different claudins have different
permeabilities
• #1 doesn’t allow H2O to pass,
#16 is permeable to Mg2+
• Important for maintaining
blood-brain barrier
Cell - Cell Interactions
• Gap junctions
– Join cytoplasmic spaces between adjacent cells via a narrow pore
• 1.5nm diameter
• 1kD cutoff, small molecules freely pass (ATP, cAMP, Ca2+, etc)
– Subunits are connexins
– Open / close regulated by phosphorylation
– Integrates cells of a tissue into a functional unit
Cell - Cell Interactions
Plant cell-cell interactions
• Plasmodesmata
– Join adjacent plant cytoplasmic spaces
– Capable of dilation, 1kD cutoff can open to a 50kD cutoff
– Exploited by some plant viruses
Roles of the plant cell wall
• Cell wall functions
– Structural role supporting and protecting plant cells
• Cellulose microfibrils confer tensile strength
– Signaling roles
• Cell wall-associated transmembrane protein kinases
– Dynamic not static, undergoes significant remodeling