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Definition

Proteolytic enzymes, released early in the course of an inflammatory response, hydrolyze fibronectin, producing fragments of the parent molecule that alter monocyte phenotype and migratory behavior1.

 

Related peptides

Two analogs of fibronectin, mimicking the 1977-1991 C- terminal part of fibronectin have been synthesized and tested. AWLI stimulated human fibronectin fragment 1977-1991, whereas AWLII hybridized to both RGD and 1977-1991 fragments2. A novel peptide sequence derived from the 33/66 kD fragments of fibronectin, FN-C/H-V (WQPPRARI), directly promotes the adhesion, spreading, and migration of rabbit corneal epithelial cells. A second peptide from the 33/66 kD fragments of fibronectin, FN-C/H-IV (SPPRRARVT), promotes rabbit corneal epithelial cell adhesion and spreading3.

 

Discovery

In 1973, Richard Hynes reported the discovery of an unknown structural protein positioned on the surface of normal cells, but which was rare or conspicuously absent on tumor cells. By the mid 1970s, Vaheri and colleagues named this protein, fibronectin (joining the Latin fibra, meaning fiber, and nectere, meaning to bind or connect). A decade after the discovery of fibronectin, Erkki Ruoslahti and colleagues identified the three-amino-acid consensus sequence that is necessary for fibronectin to attach to cells. The tripeptide, called RGD. Jacqueline Labat-Robert, M.D., a scientist at the University of Paris, suggested the fragmentation of fibronectin by proteases into smaller, free-floating fragments that possess altered chemical qualities and which are "a frequent phenomenon" of a number of pathological states, including potentially cancer 4.

 

Structural Characteristics

Fibronectin is a mosaic protein consisting of repeating sequence elements or 'modules' that are capable of folding independently (Bork et al., 1996). Its primary sequence is composed almost entirely of three types of module (F1, F2 and F3), which are organized into functional domains. These domains may be isolated in the form of proteolytic fragments that retain affinity for various ligands. Consequently, many of the ligand-binding sites have been mapped to specific regions of the fibronectin polypeptide5. 30-kDa, 50-kDa and 70-kDa gelatin-binding, 60-kDa central and 60–65-kDa heparin-binding fragments were produced by trypsin digestion of fibronectin. The secondary structure of the fragments was studied by circular dichroism and quantitative infrared spectroscopy. The structure of the 70-kDa gelatin-binding, 60-kDa central and 60–65-kDa heparin-binding fragments in solution appeared to be very close to that in the intact fibronectin. The content of the antiparallel ß-form, the only element of the secondary structure in all the fragments studied, was shown to be 30–35%6.

 

Mode of Action

120-kDa cell-binding FN fragments (FN120) decreases VLA-5 (monocyte fibronectin (FN) receptor) expression by inducing a serine proteinase-dependent proteolysis of this beta(1) integrin. Changes in VLA-5 expression, which were induced by interactions with cell-binding FN fragments, may alter monocyte migration into tissue FN, a prominent component of the cardiac extracellular matrix7.

 

The 180-kDa. fibronectin fragment both directly opsonizes particulate activators and interacts with monocyte fibronectin receptors to promote particle adherence, thereby enhancing phagocytosis through a concerted action with the distinct receptors for particulate activators8.

 

A 40 kDa carboxyl (COOH)-terminal heparin-binding fibronectin fragment containing both the III12-14 and IIICS domains (HBFN-f) can stimulate production of matrix metalloproteinases (MMPs) in normal articular cartilage explant cultures. COOH-terminal heparin-binding domain in HBFN-f is known to bind CD44, a principal hyaluronan receptor. The MMP induction by HBFN-f involves CD44 and a specific heparin-binding amino acid sequence (WQPPRARI) in HBFN-f in human normal articular cartilage. CD44 is up-regulated in articular cartilage from patients with OA [Osteoarthritis] and RA [Rheumatoid arthritis]. Increased fibronectin fragments are thought to be involved in cartilage destruction in OA and RA through their catabolic effects9.

 

Functions

Fibronectin fragments regulate the ability of monocytes to migrate through injured tissue. Evidence that FNf also induce monocyte-derived macrophages to produce agents that protect parenchymal cells against apoptosis expands its homeostatic role and indicates that, even at the outset, host responses to tissue injury may produce agents that help to limit that injury1. Fragments that bind to collagen have been isolated and have been shown to be different from those that mediate cell attachment. Heparin-binding fragments that possess neither the collagen-binding nor cell attachment functions have also been described. The binding sites for Staphylococci and fibrinogen have been located in yet another fragment at the NH2-terminal end of the molecule. The actin-binding site is located close to the collagen-binding site. The remaining active sites are known to be located in the COOH-terminal two-thirds of the polypeptide. The 200K fraction and the 170K, 100K, and 80K fragments have the same NH2-terminal sequences. They also all contain the binding site for collagen known to be located near the NH2 terminus of the fibronectin polypeptide. These results indicate that the NH2 termini of these fragments originate from the same peptide bond in the fibronectin polypeptide and extend different lengths toward the COOH-terminal end. The l00K and 80K fragments only bind to gelatin, the 170K fragment mediates cell attachment, but does not bind to heparin, while all three activities were present in the 200K fraction. The increasing number of activities in the larger fractions is not based on the large size alone, but seems to depend on the presence of distinct binding sites. The Mr = 30,000 to 50,000 heparin-binding fragments that have recently been isolated may have originated from the portion that contains the heparin-binding area in the 205K and 190K fragments. Moreover, the cell attachment-promoting activity can be separated from the gelatin-binding and heparin-binding activities, supporting the idea that a distinct binding site occupying a defined stretch of the polypeptide is also involved in this activity10.

References

 

1.     Trial J, Rossen RD, Rubio J, Knowlton AA(2004).  Inflammation and Ischemia: Macrophages Activated by Fibronectin Fragments Enhance the Survival of Injured Cardiac Myocytes. Exp. Biol. and Med., 229(6):538-545.

2.     Szaniawska B, Trembacz H, Miloszewska J, Lipkowski AW, Misicka A, Ostrowski J, Janik P(2001). Peptide analog of fibronectin that inhibits cell migration and ERK 1/2 activity. Peptides, 22(12):1949-1953.

3.     Mooradian DL, McCarthy JB, Skubitz AP, Cameron JD, Furcht LT(1993). Characterization of FN-C/H-V, a novel synthetic peptide from fibronectin that promotes rabbit corneal epithelial cell adhesion, spreading, and motility. Invest Ophthalmol Vis Sci, 34(1):153-164

4.     Longtin R (2004). Birthday of a Breakthrough: Fibronectin Research Proves Important, But Not As Originally Expected. J Natl Cancer Inst, 96(4):254-255.

5.     Pickford AR, Smith SP, Staunton D, Boyd J, Campbell ID (2001). The hairpin structure of the 6F11F22F2 fragment from human fibronectin enhances gelatin binding. The EMBO Journal, 20(7):1519-1529.

6.     Venyaminov SYu, Metsis ML, Chernousov MA, Koteliansky VE(1983). Distribution of secondary structure along the fibronectin molecule. Eur. J. Biochem, 135(3):485-489.

7.     Trial J, Baughn RE, Wygant JN, McIntyre BW, Birdsall HH, Youker KA, Evans A, Entman ML, Rossen RD(1999). Fibronectin fragments modulate monocyte VLA-5 expression and monocyte migration. J Clin Invest, 104(4):419-430.

8.     Czop JK, Austen KF(1982). Augmentation of phagocytosis by a specific fibronectin fragment that links particulate activators to the fibronectin adherence receptor of human monocytes. J Immunol., 129(6):2678-2681.

9.     Yasuda T, Kakinuma T, Julovi SM, Yoshida M, Hiramitsu T, Akiyoshi M, Nakamura T(2004). COOH-terminal heparin-binding fibronectin fragment induces nitric oxide production in rheumatoid cartilage through CD44. Rheumatology, 43(9):1116-1120.

10.   Ruoslahti E, Hayman EG, Engvall E, Cothran WC, Butler WT(1981). Alignment of Biologically Active Domains in the Fibronectin Molecule. J Biol. Chem., 256(14):7277-7281.

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Product Name Catalog # Unit Price/Unit 
490 MMP FRET Substrate III
DABCYL - RPLALWRS - EDANS
14461-01 1 mg $215 cart inquire
Fibrinolysis Inhibiting Factor
GPRP
11044-01 1 mg $175 cart inquire
Fibrinolysis Inhibiting Factor
GPRP
11044-05 5 mg $120 cart inquire
Fibrinopeptide B, Bovine
QFPTDYDEGQDDRPKVGLGAR
11056-01 1 mg $295 cart inquire
Fibronectin Binding Protein Peptide, D3 Peptide
FNKHTEIIEEDTNKDKPSYQFGGHNSVDFEEDTLPKV
11048-01 1 mg $300 cart inquire
Fibronectin Precursor (561 - 599), mouse, rat; Fib
CQDSETRTFY
11047-01 1 mg $195 cart inquire
GGGGRGDS
GGGGRGDS
11060-01 1 mg $210 cart inquire
GRADSPK
GRADSPK
11045-01 1 mg $175 cart inquire
GRGDK, FAM-labeled
GRGDK(5-FAM)
11061-01 1 mg $300 cart inquire
GRGDS
GRGDS
11049-01 1 mg $200 cart inquire
GRGDS
GRGDS
11049-05 5 mg $120 cart inquire
GRGDS amide
GRGDS-amide
13699-05 5 mg $120 cart inquire
GRGDS, amide
GRGDS-CONH2
11050-01 1 mg $200 cart inquire
GRGDS, amide
GRGDS-amide
13699-01 1 mg $65 cart inquire
GRGDS LC-biotin labeled
Biotin-LC-GRGDS
11058-01 1 mg $120 cart inquire
GRGDSP
GRGDSP
11039-01 1 mg $120 cart inquire
GRGDSP
GRGDSP
11039-05 5 mg $120 cart inquire
GRGDSPK
GRGDSPK
11051-01 1 mg $120 cart inquire
GRGDTP
GRGDTP
11040-01 1 mg $180 cart inquire
GRGDTP
GRGDTP
11040-05 5 mg $138 cart inquire
GRGESP
GRGESP
11041-01 1 mg $120 cart inquire
GRGESP
GRGESP
11041-05 5 mg $138 cart inquire
GRGETP
GRGETP
11042-01 1 mg $180 cart inquire
Heparin-Binding Peptide V, scrambled
RPQIPWAR
11062-01 1 mg $210 cart inquire
Integrin Binding Peptide
Ac-GCGYGRGDSPG-CONH2
11059-01 1 mg $120 cart inquire
Necrofibrin Hexapeptide, human
GAVSTA
11043-01 1 mg $175 cart inquire
[Phe1376] - Fibronectin Fragment (1371 - 1382)
RQDRVFHSRNSI
11046-01 1 mg $210 cart inquire
TP508, Thrombin-derived Peptide
AGYKPDEGKRGDACEGDSGGPFV
11057-01 1 mg $300 cart inquire

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