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Type 1 module T^pe 2 moduli T>pC 3 moduli

Figure 2 FN structure and domain organization. The modular structure of FN shows the position of the types 1, 2 and 3 modules. The positions of the alternatively spliced regions EDA, EDB and IIICS, which contain integrin-binding sites, are shown. The ninth type III module contains the synergy region. The tenth type III module contains the RGD sequence involved in integrin binding. The IDAPS sequence located near the carboxyl terminus of the heparin-binding domain of FN is involved In integrin binding. The other binding sites with the counterpart ligands are indicated by square brackets.

Fibronectin expression and distribution

FN is present in all body fluids and most abundantly in plasma (330-350 pg ml-1). It is also widely distributed in the basement membranes and in the connective tissue matrices throughout the body, where it is expressed together with other ECM proteins. Cellular FN is mainly synthesized by fibroblasts and tissue macrophages. Chondrocytes, myoblasts, endothelial cells, astrocytes, Schwann cells, hepatocytes, kidney cells and keratinocytes also produce FN. Resting platelets, neutrophils and monocytes do not express surface FN, but they produce and release it upon activation during hemostasis and inflammation; T lymphocytes and natural killer (NK) cells constitutively synthesize and secrete FN.

Fibronectin ligands

FN interacts with a large number of molecules and ECM components including collagens, fibrin, fibrinogen, proteoglycans, and factor VIII via specific binding sites (Figure 2). FN specifically interacts with collagens (most strongly with collagen type III) and gelatin. FN binding to fibrin occurs on at least two different sites and plays an important role in the formation of blood clots and cryoprecipitates in the plasma. FN also interacts with and is a substrate for factor VIII. Factor VIII cross-links FN to fibrin during blood clotting and induces cross-linking of FN to collagen and bacteria. FN interaction with heparin involves two specific sites in the C- and N-rermini. FN interaction with gangliosides, phospholipids, Clq complement component, acetylcholinesterase and thrombospondin have been reported. Cell adhesion to FN is mostly mediated by cell surface receptors belonging to the integrin family. Integrins represent a large group of heterodimeric receptors that are of central importance in cell surface interactions between many cell types and a variety of ECM proteins including FN. Each integrin is composed of a and 3 subunits which are membrane glycoproteins with a large extracellular domain, a single membrane-spanning segment and a short cytoplasmic portion. Divalent cations regulate the association of a and (5 subunits and ligand binding. The extracellular portion of integrins binds to ligands, whereas the cytoplasmic domain interacts with cytoskeletal elements. A general model of the integrin structure is presented in Figure 3.

The RGD sequence specifically binds to a,Pi, «,(3,, av(3|, avp.?, allb(35, av|3s, and av|3h. The allbp ,-integrin can also interact with an 11 residue peptide present in the ninth type III module. The IIICS domain, with the adhesive sequences EILDVPS in the CS1 region and REDV in the CS5 region, and the adjacent heparin-binding domain, with the IDAPS sequence, provide the binding region for a4(i| and a4p7 integrins. The FN-binding integrins and FN recognition sequences are shown in Figure 4.

Extracellular region

Cytoplasmic region

Extracellular region

Cytoplasmic region

Figure 3 Integrin structure and domain organization. The N-terminal sequences of oi and (3 subunits contribute to the ligand-binding site. The extracellular portion of the a subunit is characterized by the presence of a region which binds divalent cations. The l-domain is present only in some « subunits The a subunits without an l-domain undergo intracellular proteolytic processing. The resulting heavy and light chains remain bound by a disulfide bridge. The (3 subunit is characterized by four cysteine-rich repeats and by an l-domain-like sequence.

Cytoskeleton

Cytoskeleton

Figure 3 Integrin structure and domain organization. The N-terminal sequences of oi and (3 subunits contribute to the ligand-binding site. The extracellular portion of the a subunit is characterized by the presence of a region which binds divalent cations. The l-domain is present only in some « subunits The a subunits without an l-domain undergo intracellular proteolytic processing. The resulting heavy and light chains remain bound by a disulfide bridge. The (3 subunit is characterized by four cysteine-rich repeats and by an l-domain-like sequence.

Fibronectin and signaling

Engagement of FN receptors by FN or specific antibodies initiates biochemical signaling events within the cell important for regulating different cell functions such as migration, adhesion, proliferation, differentiation, apoptosis and specific gene expression. Recently, a variety of potential signaling mediators activated by FN interaction with integrins have been identified in many cell types: they include the focal protein tyrosine kinase FAK (ppl25MK), the serine-threonine kinases PKC and MAPK, the adapter molecules SHC and GRB-2, the GTP-binding proteins p21 RAS and RHO, the phosphatidylinositol 3-kin-ase (PI3K). FN binding can also trigger other events, such as elevation of intracellular pH and Ca2+ transients. The FN signaling pathways are shown in Figure 5.

Fibronectin and development

Mutations of FN and FN-binding integrin genes in the mouse have provided exciting insights into their function during morphogenesis. Null mutations in either FN or the integrin ols gene lead to embryonic lethality. FN-null embryos develop abnormalities shortly after gastrulation. Defects are found in mesodermal derivatives along the anterior-posterior axis and in the yolk sac vasculature. Mutant embryos lack notochord and somites along the entire axis, although precursors for these tissues are present.

Fibronectin, cell growth and apoptosis

Cellular interaction with FN promotes cell cycle progression and proliferation by affecting cyclins and immediate early response genes. Clustering of a,-ß, fibronectin receptor induces an increase in CDK-2 and CDC-2-dependent kinase activity accompanied by hyperphosphorylation of the retinoblastoma protein, Rb. In addition, cell adhesion to FN results in a rapid induction of c-fos and c-myc transcripts. FN is also involved in cell survival and protection from apoptosis in many cell types, including epithelial and endothelial cells and leukocytes. In human endothelial cells FN or FN-binding integrins, which trigger the RAS-MAPK pathway via SHC.", arrest apoptotic cell death even in absence of mitogens; in Chinese hamster ovary (CHO) cells increased expression of Bcl-2 gene, which is a potent antagonist of apoptosis, is specifically induced by ct,-ß, ligation; adhesion to FN via a,4ß, prolongs eosinophil

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