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 Matrix (ECM)
An organized network of materials located beyond the plasma membrane

3. Basement membranes Thick regions of ECM Surround muscle/fat
Underlie the basal surface of epithelial tissues

4. Basement membranes Separate different tissues
Provide mechanical support
Barrier to macromolecule and cellular movement
Substrate for cell migration
Generate signals that maintain cell survival

5. 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

6. 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)

7. ECM and disease Diseases caused by defects in collagen genes
Osteogenesis imperfecta
Fragile bones
Ehlers-Danlos syndrome
Hyperflexible joints,
highly extensible skin

8. ECM: Proteoglycans
Protein core + glycosaminoglycan (GAG) polysaccharide complex
High amount of negative charge binds cations and H2O
Hydrated gel resists compressive forces
Hyaluronic acid links many proteoglycans to form large molecules
Fill the scaffold created by collagens

9. ECM: Fibronectins Modular domains for interactions
Bind collagens, proteoglycans, integrins at cell surface
NC cells

10. 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

11. ECM Remodeling Matrix metalloproteinases (MMPs)
Degrade ECM proteins to enable:
Tissue remodeling
Cell migration
Wound healing

12. Steps leading to metastatic spread
MMP activity

13. Cell - ECM Interactions
Plasma membrane
talin
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

14. Inactive

15. Active

17. Cell – ECM: Integrins Ligand binding
RGD loop of Fibronectin binds to integrin receptor extracellular domain
Isolated RGD Loop can be exploited to block platelet aggregation / blood clotting

18. Cell – ECM: Integrins 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

19. Cell – ECM: Integrins 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)

20. Forces exerted by focal adhesions

21. Cell – ECM: Integrins Structures important for adhesion to substrate
Hemidesmosome
more permanent anchor to basement membrane
Integrins bound to laminin to dense collection of intermediate filaments

22. ECM and disease Disease: epidermolysis bullosa
Epidermis poorly connected to basement membrane / dermis
Fluid accumulates in between = blister
(keratins)

23. Cell - ECM Interactions

24. 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

25. 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 to the cytoskeleton

26. 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)

27. Cell - Cell Interactions
Tight junctions
Seal two membranes together
Block paracellular movement
Occludin and claudins (24 genes)
Important for maintaining blood-brain barrier

28. 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

30. Cell - Cell Interactions

31. 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

32. Roles of the plant cell wall
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