The EIIIA Segment of Fibronectin Is a Ligand for Integrins alpha 9beta 1 and alpha 4beta 1 Providing a Novel Mechanism for Regulating Cell Adhesion by Alternative Splicing

  • Liao Y
  • Gotwals P
  • Koteliansky V
 et al. 
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Alternative splicing of the fibronectin gene transcript gives rise to forms that include the EIIIA (or ED-A) seg-ment. EIIIA-containing fibronectins are prominently ex-pressed during embryogenesis and wound healing and appear to mediate changes in cell adhesion and gene expression. Nonetheless, integrins that bind the EIIIA segment have not been identified. We previously mapped the epitope for two function-blocking mono-clonal antibodies to the C-C؅ loop region of the EIIIA segment (Liao, Y.-F., Wieder, K. G., Classen, J. M., and Van De Water, L. (1999) J. Biol. Chem. 274, 17876 –17884). The sequence of this epitope (39 PEDGIHELFP 48) resem-bles the sequence within tenascin-C to which the inte-grin ␣ 9 ␤ 1 binds. We now report that either integrin ␣ 9 ␤ 1 or ␣ 4 ␤ 1 can mediate cell adhesion to the EIIIA segment. Moreover, this interaction is blocked both by epitope-mapped EIIIA antibodies as well as by the respective anti-integrins. Deletion mutants of the EIIIA segment that include the C-C؅ loop and flanking sequence bind cells expressing either ␣ 9 ␤ 1 or ␣ 4 ␤ 1 . Adhesion of ␣ 4 ␤ 1 -containing MOLT-3 cells to the EIIIA segment stimu-lates phosphorylation of p44/42 MAP kinase. Our obser-vation that two integrins bind the EIIIA segment establishes a novel mechanism by which cell adhesion to fibronectin is regulated by alternative splicing. Although it has been clear for many years that fibronectin (FN) 1 is alternatively spliced, the functions of, and receptors for, two alternatively spliced segments termed EIIIA (or ED-A) and EIIIB (or ED-B) segments have remained elusive. More is known about a non-homologous IIICS repeat encoding the CS-1 segment, which is a cell adhesive site and ligand for integrin ␣ 4 ␤ 1 (1). Both the EIIIA and EIIIB segments are homologous FN type III repeats and are prominently expressed during

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  • Yung-Feng Liao

  • Philip J Gotwals

  • Victor E Koteliansky

  • Dean Sheppard

  • Livingston Van De Water

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