Integrin αβ as a negative regulator of the laminin receptors αβ and αβ.

Integrin αβ is a widely expressed collagen I receptor which also mediates laminin-111 binding in some cell types, but the functional relevance of collagen versus laminin binding for different cell types is poorly understood. Here we use AFM-based singe-cell force spectroscopy (SCFS) to compare αβ-mediated adhesion strength to collagen and laminin in different cell types. Chinese Hamster Ovary (CHO) cells stably expressing integrin αβ (CHO-A2) displayed enhanced adhesion to collagen, but weak adhesion to laminin, consistent with a role of αβ as a receptor only for collagen in these cells. Inversely, the αβ-deficient CHO wildtype cells (CHO-WT) showed weak adhesion to collagen, but strong adhesion to laminin-111, in turn suggesting that integrin αβ expression suppresses laminin binding. Analogous results were obtained in a pair of SAOS-2 human osteosarcoma cell lines. Again, wildtype cells (SAOS-WT) adhered strongly to laminin and poorly to collagen, while expression of integrin αβ (SAOS-A2) induced strong adhesion to collagen, but reduced adhesion to laminin. Expression of αβ also shifted cell spreading preference from laminin to collagen and suppressed laminin-dependent transmigration. In agreement with reduced laminin adhesion, αβ expression downregulated transcription and expression of integrin subunits α and β, components of the main laminin-111 binding receptors integrin αβ and αβ in these cells. Integrin α and β expression was also reduced when α expression was chemically induced using tetradecanoyl-phorbol-acetate (TPA). Our results thus show that integrin αβ expression negatively regulates integrin αβ and αβ-mediated adhesion, spreading and invasion on laminin in different cancer cell types. In contrast to SAOS-WT, but similar to SAOS-A2 osteosarcoma cells, primary Human osteoblasts (HOB) cells express α but only low levels of β integrin, preferentially adhere to and spread on collagen over laminin and show suppressed laminin-dependent transmigration. By enhancing collagen binding directly and suppressing laminin binding indirectly through laminin receptor downregulation, αβ expression may thus re-direct migrating cancer cells from laminin-rich to collagenous tissues and partially revert osteosarcoma cells towards an untransformed phenotype.