fibronectin

Fibronectin (FN) is a high molecular weight, multidomain glycoprotein, comprising about 5% by weight of carbohydrate.

Fibronectin exhibits diverse recognition functions located on distinct fragments or domains, so FN can interact with a variety of macromolecules including/on :
● cytoskeleton
● extracellular matrix – collagen, glycosaminoglycans, proteoglycans, tenascin, fibulin and thrombospondin
● circulating coagulation factors – Fn is covalently incorporated into fibrin clots through the transglutaminase action of coagulation factor XIII, improving fibroblast adhesion
● fibrinolytic system
● acute phase proteins
● complement system
● cell-surface receptors on a variety of cells including fibroblasts, neurons, phagocytes and bacteria – integrins (through RGD tripeptide)
● itself, forming fibrillar entities
● small molecules such as gangliosides, sugars, and Ca ions.

Fibronectin (FN) participates in tissue repair, embryogenesis, blood clotting, and cell migration/adhesion. Cells of most tissues synthesize fibronectin. Soluble fibronectin is produced by hepatocytes and circulates, in its disulfide-bonded dimeric form, in the plasma. The soluble protomer is a compact, flexible dimer that can be converted into an insoluble, fibrillar network. The soluble-to-fibrillar conversion is a highly regulated process involving integrins and possibly other cell-surface receptors [ref] including uPAR (urokinase-type plasminogen activator receptor) [ref] and a cell-surface proteoglycan [ref].[s]

The insoluble fibronectin dimer is synthesized by fibroblasts, chondrocytes, endothelial cells, macrophages, as well as certain epithelial cells. Electron microscopic analyses of natural thin fibrils (5-18nm diameter), made by fibroblasts in culture, clearly indicate an ordered arrangement and suggest a model in which extended protomers (130nm long) are arranged end-to-end with an overlap of about 14 nm [ref]. As an extracellular adhesion molecule, FN binds to integrins and participates in wound healing.

Cell-surface receptors or fibrinogen, collagen and fibrin (as extracellular matrix proteins) facilitate the adherence of microorganisms to host tissues [ref]. The Hep-2 domain of fibronectin interacts with envelope glycoproteins on some retroviruses. Fibronectin is able to bind both the virus and cell-surface receptors, concentrating viruses on the surface of the cells, enhancing viral uptake by cells.

The structural isoforms of fibronectin arise from alternative splicing of a single gene, and possess a variable region plus three types of repeated internal regions (homologous, repeating modules I, II and III) +/- disulfide bonds.

[more] [] The Type I module of fibronectin [] The Type II module (F2) [] segment of fibronectin , four Type III modules []

tags [Proteins] [fibronectin]

| 0 Guide-Glossary

scaffold proteins

Scaffold proteins either hold protein kinases in a latent state close to their activating cell-surface receptors, or facilitate flow of activation from one kinase to the next kinase in a signaling cascade.

The A kinase anchoring proteins (AKAPs) are prototypical scaffold proteins that organize the protein kinases and phosphatases that regulate serine/threonine phosphorylation: 'Multiprotein signaling networks create focal points of enzyme activity that disseminate the intracellular action of many hormones and neurotransmitters. Accordingly, the spatio-temporal activation of protein kinases and phosphatases is an important factor in controlling where and when phosphorylation events occur. Anchoring proteins provide a molecular framework that orients these enzymes towards selected substrates. A-kinase anchoring proteins (AKAPs) are signal-organizing molecules that compartmentalize the cAMP dependent protein kinase, phosphodiesterases, and a variety of enzymes that are regulated by second-messengers.'[s].

In an example of scaffold mediated assembly of signaling pathways, Jip1 has separate binding sites for Jnk, and for the upstream kinases MKK7 (MAPKK), MLK3 (MAPK), and HPK1, enabling Jip1 to act as a scaffold for the mammalian Jnk MAPK cascade. Jip1 also possesses SH3 and PTB domains that can tether the complex to additional proteins participating in upstream activation or localization. B

ERK MAPK docks to target proteins and phosphorylates the substrate, Rsk1.

The regulatory cyclin A subunit of CDK2 binds substrates with a conserved RXL motif, such as p107.

The AKAP protein Yotiao binds the NMDA receptor, inactive PKA, and active PP1. Thus, Yotiao brings together components that repress resting NMDA receptor and enhance channel activation.[s]

| 0 Guide-Glossary