Fig. 19-1 Simplified drawing of a cross-section through part of the wall of the intestine . Each tissue is an organize

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: MajorPlasma 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. 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 INTEGRINS 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 CollagenFIBRILS 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 Cell Suface Binding Sites J. Anat. 193:1, ‘98

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. Matrix Metalloproteases Genes Dev 14:2123,’00

35. Genes Dev 14:2123,’00

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

37. Trends Genet. 16:83, ‘00