1. 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)

2. 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

3. The Extracellular Matrix (ECM)
An organized network of materials located beyond the plasma membrane

4. The Extracellular Matrix (ECM)
Basement membranes
Thick regions of ECM
Surround muscle/fat
Underlie the basal surface of epithelial tissues

5. 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

6. 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

7. 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)

8. The Extracellular Matrix (ECM)
Diseases caused by defects in collagen genes
Osteogenesis imperfecta
Fragile bones
Ehlers-Danlos syndrome
Hyperflexible joints, highly extensible skin

9. 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

10. 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

11. 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

12. ECM Remodeling Matrix metalloproteinases (MMPs)
Enzymes that degrade ECM proteins
Tissue remodeling
Cell migration
Wound healing

13. Steps leading to metastatic spread
MMP activity

14. 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

15. Inactive

16. Active

18. 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

19. 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

20. 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)

21. Forces exerted by focal adhesions

22. 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

23. 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
(keratins)

24. Cell - ECM Interactions

25. 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

26. 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

27. 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)

28. 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

29. 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

31. Cell - Cell Interactions

32. 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

33. 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