2. Fig. 19-1 Simplified drawing of a cross-section through part of the wall of the intestine. Each tissue is an organized assembly of cells held together by cell-cell adhesions, extracellular matrix, or both.

3. CELL-CELL ADHESION Largely self-study:  types of cell-cell adhesive interactions [junctional: occluding (tight), adherens, desmosomes & gap; + nonjunctional]  constituents (plasma membrane and cytoskeletal, if any) and structures of each type of cell-cell interaction  functional roles of each type of cell-cell adhesion

4. A Summary of Junctional and Nonjunctional Adhesion Fig. 19-28

5. Cell-Cell Adhesion: Major Plasma Membrane Proteins Junction Protein family Tight Occludins & claudins (not in text) Adhesion Cadherins, e.g., E-cadherin Desmosome Cadherins Gap Connexins nonjunct. Ig-like, e.g., N-CAM nonjunct. Selectins*, e.g., E-selectin nonjunct. Integrins* * cell-cell adhesion in a limited number of cell types

6. Functions of Tight Junctions  Restricts movement of plasma membrane proteins & lipids between the apical and basolateral membranes  Barrier to diffusion of molecules across the epithelial cell sheet Fig. 19-3A

7. EXTRACELLULAR MATRIX (ECM)  Extracellular network of macromolecules  Components secreted locally; organized by cells associated with the matrix Fig. 19-31

8. BASAL LAMINA  Flexible, thin mat of specialized ECM  Often termed basement membrane  In close association with cells, as illustrated at right, Fig.19-53.

9. MAJOR ECM CONSTITUENTS  Hyaluronan  Proteoglycans  Collagens  Elastin  Fibronectin  Laminin  Enactin/ nidogen Fig. 19-57 Protein in green, glycosaminoglycan in red.

10. Plasma Membrane Constituents which Bind to the ECM  Integrins  Proteoglycans Fig. 19-28

11. INTEGRINS  Plasma membrane heterodimers  Have ECM or surface membrane binding domain(s)  Have divalent cation binding sites  Many participate in linking the ECM to the cytoskeleton Fig. 19-60

12. Circ Res 89:211. 2001

13. Integrins and their ligands J Biol Chem 275:21785, 2000

14. J Biol Chem 275:21785, ‘00

15. PLASMA MEMBRANE PROTEOGLYCANS Annu Rev Biochem 68:729,’99

16. HYALURONAN Fig. 19-35 Disaccharide structure Fig. 19-34 Relative volumes

17. Table 19-3 Some Common Proteoglycans

18. COLLAGENS  A helix comprised of homotrimer & heterotrimer polypeptides (alpha chains)  Major proteins of ECMs  Many different alpha chains  Multiple structures (involves cross-linking of chains) –fibrils –network forming –fibril-associated Fig. 19-40

19. Table 19-4 Some types of collagen & their properties

20. Formation of Collagen FIBRILS and FIBERS Fig. 19-43

21. Formation of Collagen Networks Fig. 19-52

22. COLLAGEN ASSEMBLIES Ann Med 33:7, 2001

23. ELASTIC FIBERS  Elastin, main constituent  Fibers crosslinked to form a network  Fibers & network can extend and recoil Fig. 19-50

24. MICROFIBRILS  Cover elastin core of elastic fibers  Also found in other extracellular matrices  Contain glycoproteins including fibrillin

25. FIBRONECTIN (FN)  Extracellular dimeric glycoprotein  Differential splicing  Multiple functional domains –cell binding RGD sequence of FN other specificities –heparin binding –collagen binding –fibrin binding  Organized into a matrix Fig. 19-51 A,C

26. LAMININ  Heterotrimeric glycoprotein  Basal lamina constituent  Multiple binding domains Fig. 19-55

27. Binding Domains of Laminin  Self assembly  Type IV collagen  Heparan sulfate  Enactin/nidogen  Cell Surface –integrin –nonintegrin J. Anat. 193:1, ‘98 Cell Suface Binding Sites

28. BASAL LAMINA Fig. 19-56

29. HEMIDESMOSOMES  Junctions linking the intermediate filaments to the ECM  Constituents include –integrins –other plasma membrane proteins –cytosolic proteins  Functions include –adhesion –intracellular signaling Bioessays 20:488, ‘98

30. Focal Adhesion (Focal Contact or Adhesion Plaque)  Junctions linking actin filaments to the ECM  Constituents include –integrins –cytosolic proteins  Functions include –adhesion –cell signaling Fig. 16-75B

31. INTEGIN-ECM SIGNALING “inside-out” signals (1-3) Biochem J 339:481, ‘99 Curr Opin Cell Biol 11:634, ‘99

32. Diversity in Adhesive Interactions  Diversity in the major components due to: –differential splicing –post-translational modifications –different gene products  Participation of additional molecules

33. Matrix Metalloproteases  Also termed matrix metalloproteinases, matrixins, MMPs  Enzymes which cleave ECM constituents, including collagenases  Contain a propeptide which must be cleaved for enzyme activity  Multiple mechanisms to regulate MMP activity, including inhibition by tissue inhibitors of metalloproteases (TIMPs)  Other functional domains

34. Genes Dev 14:2123,’00 Matrix Metalloproteases

35. Genes Dev 14:2123,’00

36. ADAM A Disintegrin And Metalloprotease Trends Genet. 16:83, ‘00 A disintegrin is a molecule that binds to an integrin. T = transmembrane domain

37. Trends Genet. 16:83, ‘00