Integrin α6β4E variant is associated with actin and CD9 structures and modifies the biophysical properties of cell-cell and cell-extracellular matrix interactions

Abstract

Integrin alpha 6 beta 4 is an essential, dynamic adhesion receptor for laminin 332 found on epithelial cells, required for formation of strong cell-extracellular matrix (ECM) adhesion and induced migration, and coordinated by regions of the beta 4C cytoplasmic domain. beta 4E, a unique splice variant of beta 4 expressed in normal tissue, contains a cytoplasmic domain of 231 amino acids with a unique sequence of 114 amino acids instead of beta 4C's canonical 1089 amino acids. We determined the distribution of alpha 6 beta 4E within normal human glandular epithelium and its regulation and effect on cellular biophysical properties. Canonical alpha 6 beta 4C expressed in all basal cells, as expected, while alpha 6 beta 4E expressed within a subset of luminal cells. alpha 6 beta 4E expression was induced by three-dimensional culture conditions, activated Src, was reversible, and was stabilized by bortezomib, a proteasome inhibitor. alpha 6 beta 4C expressed in all cells during induced migration, whereas alpha 6 beta 4E was restricted to a subset of cells with increased kinetics of cell-cell and cell-ECM resistance properties. Interestingly, alpha 6 beta 4E presented in "ringlike" patterns measuring similar to 1.75 x 0.72 microns and containing actin and CD9 at cell-ECM locations. In contrast, alpha 6 beta 4C expressed only within hemidesmosome-like structures containing BP180. Integrin alpha 6 beta 4E is an inducible adhesion isoform in normal epithelial cells that can alter biophysical properties of cell-cell and cell-ECM interactions.