Chapter 22: Integrating Cells into Tissues

 

Cell-Cell adhesion:

·      Types of cell adhesion molecules (CAMs) (22-2) - Cadheins, Ig superfamily CAMs, selectins, mucins and integrins.

·      Types of junctions – tight junction, gap junction, cell-cell junction (desomosome) and cell-matrix junction (semi-desmosome).

·      Cadherins – Ca⁺² dependent adhesion by dimerization of cadherins on adjacent cells; bind to other cadherins of the same type; transmembrane glycoprotein; the E, P and N cadherins functions at different times and on different cells during development; form specialized adhesion junctions.

·      N-CAMS – function in nervous system tissues; a member of the Ig superfamily of CAMs; mediate homophilic binding between similar N-CAMs on different cells; N-CAM binding is Ca⁺² independent; diverse forms created via differential splicing and glycosylation (22-3); adhesion modulated by sialic acid in the ECM, which weakens binding between N-CAMs.

·      Selectins – are lectins, which bind to carbohydrates; Ca⁺² is required for selectin binding.

·      Leukocyte extravasion – movement of leukocytes through endothelial cell layers to get to an area of infection; P selectin is present in intracellular vesicles and released to the cell surface as a response to inflammatory signals; leukocytes (monocytes, neutrophils, T and B cells) contain the carbohydrate that P selectin binds; weak binding occurs between selectin and carbohydrate, the weak bonds are then strengthened by binding among integrins; platelet activating factor (PAF) is released from endothelial cells and binds to PAF receptors on the leukocyte which activates a_Lb₂ integrins on the cell surface; a_Lb₂ integrins bind to I-CAMs on the endothelial surface to form a tight bond; once a tight bond is formed the leukocyte moves between endothelial cells (22-4).

·      Adherins junctions and desmosomes (22-5) – adherins junctions are found in epithelial cells just below tight junctions; cadherins are the CAMs in adherins junctions; cadherins bind to a and b catenin adapter proteins which then bind to actin filaments; desmosomes link adjacent cells (226); desmoglein and desmocollin are the cadherins in desmosomes; plakoglobin functions similarly to catenins; plakoglobin attaches to Keratin IFs.

·      Gap junctions – form channels that small molecules (ions, ATP, cAMP, etc.) move from one cell to the next; Ca⁺² at high levels closes Gap junctions; gap junctions are formed from six connexin proteins in each cell (12 total) which form a channel (22-8).

 

Cell-Matrix Adhesion:

·      Integrins – composed of a and b subunits; Different a/b combinations bind to different cell surface or cell matrix ligands (T22-2); integrins bind to their ligands with low affinity, which promotes efficient movement of cells during development.

·      Blood clots – a_IIbb₃ integrin on platelets becomes activated by binding collagen or thrombin and can then bind fibrinogen, which accelerates clot formation; a₄b₁ integrin binds fibronectin in the matrix and VCAM-1 in bone marrow stromal cells; decreasing a₄b₁ integrin late in development allows mature blood cells to enter circulation.

·      De-adhesion factors – when cells need to move that were formerly tightly anchored to a matrix surface; mediated by disintegrins which bind to integrins and inhibit their binding; found in snake venom; cell fates are determined through structural remodeling by a disintegrin and a metalloprotease (ADAM) glycoproteins.

·      Integrin containing cell junctions (22-9) – focal adhesions connect the actin cytoskeleton to fibronectin; adapter proteins connect beta integrin to actin filaments; hemidesmosomes are typically on the basal surface of epithelia and anchor cells to the basal lamina; integrins bind to keratin fibers inside the cell through adapter proteins, and to laminin in the extracellular matrix; hemidesmosomes increase the rigidity of tissues.

 

Collagen:

·      Structure of Collagens – collagens are comprised of three classes (T22-2); all collagen types have a triple helical structure; collagen I is the classic example that forms long collagen fibrils (22-11); the triple helix derives from a repeated Gly-Pro-X motif; hydroxyproline is derived from proline by prolyl hydrolases and is common in collagen; collagen fibrils interact laterally to form fibers; lateral interactions are mediated by covalent aldol crosslinks between lysine/hydroxylysine residues at the N and C termini (22-12).

·      Synthesis (22-14) – procollagen is synthesized in the ER and modifications to this protein are important for fibril formation; aldol crosslinks and formation of fibers is completed in the ECM; prolyl hydrolases require Vitamin C to function, and lack of vitamin C causes scurvy which diminishes the structural integrity of your body; mutations in collagen I or defects in expression of collagen subunits lead to bone and/or other crippling diseases.

·      Structures that collagens make – fibril associated collagens include type IX, which are flexible, kinked, and form links to other components of the ECM (forming cartilage) and type VI which links fibers together (interstitial tissues) (22-16); type IV collagen forms the basal lamina that underlies sheets of cells; type IV collagen has a kinked structure and forms sheets through lateral and C-terminal associations (22-17).

 

Non-collagen ECM components:

·      Laminin – major structural element of basal laminae (22-20); composed of three subunits that interact with various ECM components (22-19); basal lamina is secreted by the tissues they support (22-21).

·      Fibronectin – attaches cells to fibrous collagen matrices; can control cells shape and migration during development; composed of dimers that have binding sites for many ECM components and cell surface molecules (22-22); an RGD sequence is sufficient for binding integrins; circulating fibrinogen contributes to blood clotting by binding to fibrin and attracting activated platelets through integrin binding.

·      Proteoglycans – glycosaminoglycans (GAGs) linked to a core protein; glycosaminoglycans consist of chondroitin sulfate, heparin sulfate and keratan sulfate (22-24); GAGs are linked to the protein at serine residues through Xyl-Gal-Gal linkers (22-25).

·      ECM proteoglycans – aggrecan forms large proteoglycan aggregates and is found in cartilage; the N terminal domain binds with a link protein to hyaluronin to form aggregates (22-26); help to cushion and resist deformation.

·       Cell-surface proteoglycans - typically on epithelial cells; have a transmembrane domain; most common is syndecan (22-27); function to anchor cell to matrix and mediate growth factor presentation.

·       Growth factor control – ECM and cell surface proteoglycans having heparin sulfate control activity and presentation of growth factors such as FGF (22-28); growth factors are sequestered by proteoglycans, thus forming a reservoir of growth factor; when heparin sulfate chains are released via proteolysis of the core protein or degradation of the side chain, the growth factor can then bind to the receptor.

·       Hyaluronin – not bound to a protein core; because it contains anionic residues it binds to water to form a gel; functions to cushion; promotes cell migration by binding cells through CD44 and keeping them apart; cessation in movement correlates with release of hyaluronidase and reduction in CD44, thus allowing cell-cell contact.