Fibronectin

Abstract

In the past 2 decades, it has been appreciated that the functions of the extracellular matrix (ECM) are not entirely structural. ECM components interact with specific adhesion receptors on cell surfaces and regulate various cellular functions, including differentiation, proliferation, migration, and apoptosis. Fibronectin (FN) is a paradigm adhesive protein, nonreactive with adhesion receptors in its soluble state but highly adhesive when insoluble. Polymerization of FN into the ECM must be tightly regulated to ensure that the adhesive information in the ECM is appropriate.FN exists in a soluble protomeric form in micromolar concentration in blood plasma and in an insoluble multimeric form in the ECM.1,2 Unlike fibrillar or basement membrane collagens, laminins, actin, and tubulin, circulating FN does not self-polymerize in physiologically relevant solutions. Furthermore, there is little passive accumulation of FN in preexisting ECM. Rather, assembly of FN takes place at specialized areas on the cell surface.3 FN is especially abundant in the ECM of embryonic and regenerating or injured tissues, although it can be found in most ECMs, including basement membranes. FN interacts with cells through integrins, heterodimeric transmembrane receptors linking the ECM to the intracellular cytoskeleton and signaling pathways. The aim of this review is to describe the mechanisms and consequences of FN deposition and give a brief overview of the significance of FN for selected areas of cardiovascular research. In the first section we describe important features of the FN molecule that account for its multiple functions. Next, we focus on the assembly process, ie, the conversion of soluble FN to its active, adhesive, insoluble form. Finally, we discuss several areas of cardiovascular research in which FN may have an important role, exemplifying how the adhesive information of FN can drive pathophysiological processes. Structure of FNSoluble FN is a dimeric glycoprotein. Each subunit is a mosaic of a series of repeating modules: 12 type I modules, 2 type II, 15 to 17 (depending on splicing) type III, and a variable (V) sequence that is not homologous to other parts of FN (Figure 1). The deduced amino acid sequences for FNs of the clawed frog and rat are well conserved, possessing 71% amino acid identity and the same overall organization. 4 The 2 type III modules that are subject to alternative splicing are called ED-A (ED for "extradomain") and ED-B. Plasma FN is synthesized in the liver by hepatocytes and contains neither ED-A nor ED-B, whereas so-called "cellular" FN (synthesized locally in tissues) contains variable amounts of either or both ED-A and ED-B. 1,2 Furthermore, in plasma FN dimers, only 1 of the subunits contains the V region, whereas almost all cellular FN subunits contain this region. 5 FN binds to ␣ 5 ␤ 1 and ␣ IIb ␤ 3 integrins through a cell adhesive site comprising modules III8-III10. The most critical site is the Arg-Gly-Asp (RGD) sequence in III10. RGD peptides block integrin-mediated cell adhesion to FN...

Structural and Functional Analysis of the Tandem β-Zipper Interaction of a Streptococcal Protein with Human Fibronectin

“…The mass of the purified product was confirmed by MS. 15 N, 13 C-labeled SfbI-5 was produced using similar methods but using isotope-labeled minimal media.…”

“…NMR Spectroscopy-A standard suite of triple resonance experiments was performed for sequential assignment of 15 N, 13 C-labeled SfbI-5 (1 mM, pH 5.5, 10% (v/v) D 2 O, 0.02% (w/v) NaN 3 ). All were acquired using standard Bruker pulse sequences on a Bruker AVII 700 MHz spectrometer equipped with a triple resonance probe and z axis gradients at 25°C.…”

“…It is found as a disulfidelinked dimer in human plasma and in an insoluble fibrillar form as a component of extracellular matrices. Fn plays an essential role in development (13,14) and in other processes requiring cell migration, such as wound healing and tissue remodeling (15). Fn is a modular protein, and the N-terminal domain (NTD) contains a string of five Fn type I (F1) modules ( [1][2][3][4][5] F1) whose sequences are highly conserved across vertebrates (16).…”

Interaction of Calcium-bound C-reactive Protein with Fibronectin Is Controlled by pH

“…It is believed that CRP circulates in the body in its Ca 2ϩ -bound form. Fn is a multifunctional glycoprotein present in the blood in addition to being the major component of the ECM (27). Fn is also highly expressed in several tumors (28 -30).…”

“…Fn is also highly expressed in several tumors (28 -30). Fn plays key roles in cell adhesion and migration processes in various physiological events, such as wound healing, thrombosis, tissue remodeling, and cancer (27,28). Thus, understanding the nature of CRP-Fn interaction and its impact on each other's functions is of importance.…”