The extracellular matrix (ECM) is a complex network
of different combinations of collagens, proteoglycans, hyaluronic acid, laminin,
fibronectin, and many other glycoproteins, including proteolytic enzymes
involved in degradation and remodeling of the extracellular matrix.
Extracellular matrix (ECM) exists in two forms: interstitial matrix that fills
in the intercellular space and the more specialized basement membrane, which is
a thin sheet of extracellular matrix underlying the epithelium. The
Extracellular Matrix and Cell Adhesion PCR Arrays are designed to determine the
gene expression profile of the molecules involved in cell-to-cell and
cell-to-matrix interactions. See details here.
Extracellular matrix provides the microenvironment for the cells and serves
as a tissue scaffold, guiding cell migration during embryonic development and
wound repair. Beyond that, it also functions as the repository and modulator of
growth factors and cytokines, and therefore is responsible for transmitting
environmental signals to the cells.
Among proteases, the matrix metalloproteinases (MMPs) and a disintegrin and
metalloproteinase with thrombospondin motifs (ADAMTS) family are often
associated with ECM degradation and remodeling. The inhibitors of MMPs are
called tissue inhibitors of metalloproteinases (TIMPs), which are comprised of
TIMP-1, TIMP-2, TIMP-3, and TIMP-4. The interactions between these proteases and
their inhibitors play important roles in cell morphogenesis, angiogenesis,
tissue remodeling, tissue repair, tumor metastasis, cirrhosis, and arthritis.
The features of the ECM are determined both by the cells that produce the matrix
and by the cells growing in it. QIAGEN's Angiogenesis, Endothelial Cell
Biology, Epithelial-to-Mesenchymal Transition (EMT), Tumor Metastasis and
Osteogenesis PCR arrays can be utilized to study gene expression patterns
related to the ECM.
Cell adhesion is the binding of the cells to each other and to the
extracellular matrix through cell adhesion molecules (CAMs) such as integrins,
selectins, cadherins, the Ig (immunoglobulin) superfamily, and lymphocyte homing
receptors. Cell adhesion mediates cell attachment, migration, and signaling to
and from the extracellular matrix. Adhesion complexes include focal adhesions,
adherens junctions, tight junctions, desmosomes, hemi-desmosomes, and gap
junctions. For example, epithelial cells form an organized cell layer and are
closely adjoined by the above mentioned membrane structures, such as tight
junctions, adherens junctions, desmosomes, and gap junctions. In addition,
epithelial cells have an apical-basolateral polarity and attach to basement
membrane.
A focal adhesion is a large dynamic cluster of integrins and other adhesion
molecules that connect the ECM to the cytoskeleton. It transmits both mechanical
force and regulatory signals. Adherens junctions are cell-to-cell junctions
between epithelial cells and are composed of cadherins and alpha-, beta-, and
delta-catenins. Tight junctions are the connections between two adjacent cells
whose membranes are joined together. Claudins and occludins are the two major
types of protein that form tight junctions. Desmosomes are spot-like adhesions
between epithelial cells and make epithelium to resist shearing forces. The cell
adhesion proteins of the desmosome are members of the cadherin family. Rather
than linking two cells, hemi-desmosomes attach cells to the extracellular matrix
and use integrin cell adhesion proteins rather than cadherins. Hemi-desmosomes
connect the basal part of the cells to the basement membrane. Gap junctions
directly connect the cytoplasm of two cells, allowing small molecules to pass
between the two adjacent cells. In vertebrates, gap junctions are composed of
connexin proteins.
The best characterized adhesion molecules are the integrins; and the best
charaterized adhesion complexes are focal adhesions. Integrins are heterodimers
of α- and β - subunits that bind to the ECM through large extracellular domains
and connect intracellularly to the actin cytoskeleton filaments. The
extracellular ligands that anchor these adhesions include laminin, fibronectin,
vitronectin, and various collagens. Focal adhesions can be considered both as
sensors of force and as sites that originate cytoskeletal forces through
anchored actin-microfilament bundles. Focal adhesions have many SH2-containing
components (such as Src kinases, PI3K, SHP-2), as well as many tyrosine-phosphorylated
molecules (for example, focal adhesion kinase (FAK), paxillin, tensin, CAS,
SHPS-1, and caveolin). Therefore tyrosine phosphorylation of these sites, which
is induced by integrins clustering, growth factor stimulation, or applied force,
could potentially stimulate focal adhesion assembly. Inhibitors of tyrosine
phosphorylation block adhesion-complex formation and recruitment of a large
subset of focal adhesion components.
Cadherins are a superfamily of adhesion molecules that mediate
calcium-dependent cell-to-cell adhesion. Removal of calcium abolishes their
adhesive activity and renders cadherins vulnerable to proteases. There are three
major types of cadherins: E (epithelial)-cadherin, N (neuron)-cadherin and P
(placental)-cadherin. The well characterized E-cadherin binds to p120-catenin
and beta-catenin. Beta-catenin can also bind to alpha-catenin, which regulates
actin filaments. The Wnt signaling pathway is associated with the cadherin
signaling pathway through the convergence of beta-catenin. The loss of E-cadherin
often leads to tumor invasion and metastasis. In this context, a cell surface
glycoprotein, CD44, is often involved as well.
In research on E-cadherin, an important topic is epithelial-mesenchymal
transition (EMT). Epithelial cells can convert into mesenchymal cells by a
process known as EMT. In other words, mesenchymal cells can arise from
epithelial cells. During this process, epithelial cells will lose many of their
epithelial characteristics and start to display many mesenchymal features. For
example, epithelial cells express E-cadherin whereas mesenchymal cells do not.
The intermediate filament vimentin is typical of mesenchymal cells while
cytokeratin is characteristic of epithelial cells. The reverse process, known as
mesenchymal-epithelial transition (MET), has also been studied. The molecular
mechanisms that regulate EMT considerably overlap with those that control cell
adhesion, motility, invasion, survival, and differentiation.
EMT is triggered by extracellular signals such as components of ECM and
growth factors, such as TGF-beta, fibroblast growth factor (FGF), epidermal
growth factor (EGF), and scatter factor/hepatocyte growth factor. These
extracellular signals trigger the activation of intracellular effectors, such as
members of the small GTPase family - Ras, Rho, and Rac, and members of the Src
tyrosine-kinase family. These effectors orchestrate the disassembly of adhesion
complexes and changes of cytoskeletal organization. The activation of signaling
pathways also results in the activation of transcriptional regulators such as
snail (SNAI1) and slug (SNAI2), which regulate the changes in gene expression patterns that underlie EMT. A central target of these transcriptional
regulators is the repression of the E-cadherin expression, which results in the
loss of E-cadherin-dependent intercellular epithelial junctional complexes and
the abolishment of E-cadherin-mediated sequestering of β-catenin in the
cytoplasm. β-catenin then localizes to the nucleus and triggers the Wnt
signaling pathway by activating transcriptional regulation through LEF/TCF4
(lymphoid-enhancer-binding factor/T-cell factor-4). In general, EMT involves the
MAPK, TGF-beta-Smad, Wnt, Notch, NF-kappaB, Akt, FAK-Rac, Src, and RhoA
signaling pathways. You can use QIAGEN's EMT or Cytoskeleton PCR arrays
for gene expression profiling.
Complete Array List
