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 aLb2 integrins on the cell surface; aLb2 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 – aIIbb3 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.