Epithelial Integrin alpha6 beta4: Complete Primary Structure of beta4 and Variant Forms of alpha6

Abstract. The integrin alpha6 beta4 is a heterodimer predominantly expressed by epithelia. While no definite receptor function has yet been assigned to it, this integrin may mediate adhesive and/or migratory functions of epithelial cells. We have determined the complete primary structure of both the alpha6 and beta4 subunits from cDNA clones isolated from pancreatic carcinoma cell line libraries. The deduced amino acid sequence of alpha6is homologous to other integrin alpha chains (18-26%identity). Antibodies to an alpha6 carboxy terminus peptide immunoprecipitated alpha6 beta4 complexes from carcinoma cells and alpha6 beta1 complexes from platelets, providing further evidence for the association of alpha6 with more than one beta subunit. The deduced amino acid sequence of beta4 predicts an extracellular portion homologous to other integrin beta chains, and a unique cytoplasmic domain comprised of > 1,000 residues. This agrees with the structures of the beta4 cDNAs from normal epithelial cells (Suzuki, S., and Y. Naitoh. 1990. EMBO [Eur. Mol. Biol. Organ.] J. 9:757-763; Hogervost, E, I. Kuikman, A. E. G. Kr. von dem Borne, and A. Sonnenberg. 1990. EMBO [Eur. Mol. Biol. Organ.] J. 9:765-770). Compared to these structures, however, the beta4 cDNAs that we have cloned from carcinoma cells contain extra sequences. One of these is located in the 5'-untranslated region, and may encode regulatory sequences. Another specifies a segment of 70 amino acids in the cytoplasmic tail. Amplification by reverse transcription-polymerase chain reaction of mRNA indicated that multiple forms of beta4 may exist, possibly due to cell-type specific alternative splicing. The unique structure of beta4 suggests its involvement in novel cytoskeletal interactions. Consistent with this possibility, alpha6 beta4 is mostly concentrated on the basal surface of epithelial cells, but does not colocalize with components of adhesion plaques.