Fibronectin splicing

The domain structure in fibronectins is made up of a few types of peptide module that are repeated numerous times. Each of the more than 50 modules is coded for by one exon in the fibronectin gene. Alternative splicing (see p. 246) of the hnRNA transcript of the fibronectin gene leads to fibronectins with different compositions. The module that causes adhesion to cells contains the characteristic amino acid sequence -Arg-Gly-Asp-Ser-. It is these residues that enable fibronectin to bind to cell-surface receptors, known as integrins. 

Komoriya, A., Green, L. J., Mervic, M., et al. The minimal essential sequence for a major cell type-specific adhesion site (CS1) within the alternatively spliced type III connecting segment domain of fibronectin is leucine-aspartic acid-valine. J. Biol. Chem. 266 15075-15079, 1991. 

Despite the very low binding of this protein to toxin columns, the a-LTX-PTPa interaction is specific and maps onto the fibronectin domains 2 and 3 (Krasnoperov et al. 2002b). These are present in both PTPol and PTPo2, but on overexpression of these splice variants in pancreatic (3-cells, only PTPol mediates the secretory action of a-LTX (Lajus and Lang 2006). This may be because the toxin binds PTPo2 too far from the membrane and is then unable to insert into the plasma membrane. 

Fig. 20.1 Leptin receptor isoforms. Leptin receptor isoforms (Ob-Ra to Ob-Re) are the result of alternative gene splicing. Ob-Rb is considered to be the active isoform for carrying out downstream signaling. The extracellular region of the receptor is comprised of two CK (cytokine receptor domain) and three F3 (fibronectin domain) domains. The extracellular domain is followed by the transmembrane domain. The intracellular region consists of B1 (box 1) and B2 (box 2) for JAK2 binding and STAT (signal transducers and activators of transcription) binding domain.

Fig. 8. Structures of LI, MAG and PO glycoproteins. The sequences of LI (a), MAG (b) and PO (c) glycoproteins predicted from analysis of cDNA clones as well as protein in the case of PO are shown to variably include in the extracellular portions Ig-like domains, fibronectin type III repeats (hatched), a transmembrane segment and a cytoplasmic domain. Potential A-glycosylation sites are indicated (open circle). Splicing variants in the cytoplasmic domains of LI and MAG are shown (open triangle).

A FIGURE 4-15 Cell type-specific splicing of fibronectin pre-mRNA in fibroblasts and hepatocytes. The =75-kb fibronectin gene (top) contains multiple exons. The EIIIB and EIIIA exons (green) encode binding domains for specific proteins on the surface of fibroblasts. The fibronectin mRNA produced in... 

More than 20 different Isoforms of fibronectin have been identified, each encoded by a different, alternatively spliced mRNA composed of a unique combination of fibronectin gene exons. Recent sequencing of large numbers of mRNAs... 

Examples of all three types of alternative RNA processing occur during sexual differentiation in Drosophila (see Figure 12-14). Commonly, one mRNA is produced from a complex transcription unit in some cell types, and an alternative mRNA is made in other cell types. For example, differences in RNA splicing of the primary fibronectin transcript in fibroblasts and hepatocytes determines whether or not the secreted protein Includes domains that adhere to cell surfaces (see Figure 4-15). 

Ffrench-Constant, C. (1988) Patterns of fibronectin gene expression and splicing during cell migration in chicken embryos. Development 104 369-382. 

Humphries, M.J., Akiyama, S.K., Komoriya, A., Olden, K. and Yamada, K.M. (1988) Neurite extension of chicken peripheral nervous system neurons on fibronectin relative importance of specific adhesion sites in the central cellbinding domain and the alternatively spliced type 111 connecting segment. J. Cell Biol. 106 1989-1297. 

Kornblihtt, A.R., Umezawa, K., Vibe-Pedesen, K. and Baralle, R.E. (1985) Primary stmcture of human fibronectin differential splicing may generate at least ten polypeptides from a single gene. EMBOJ. 4 1755-1759. 

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