Dean Sheppard

Members of the integrin family recognize a variety of spatially-restricted extracellular ligands. Classically, ligation of integrins activates cytoplasmic signals in the integrin-expressing cell and contributes to cell adhesion, migration, proliferation and survival. At least two members of this family, αvβ6 and αvβ8 perform an additional function, activation of latent complexes of transforming growth factor β. In effect, this process allows integrins on one cell to activate signals on adjacent (in the case of αvβ6) or nearby cells (in the case of αvβ8). Integrin-mediated TGFβ activation has been shown to play important roles in modulating tissue fibrosis, acute lung injury and pulmonary emphysema. Given the important roles that TGFβ plays in modulating epithelial cell growth, epithelial-to-mesenchymal transformation and tumor invasion and metastasis, integrin-mediated TGFβ activation is likely to play important roles in tumor growth ad metastasis.

The integrin α9β1 is expressed on migrating cells, such as leukocytes, and binds to multiple ligands that are present at sites of tissue injury and inflammation. α9β1, like the structurally related integrin α4β1, mediates accelerated cell migration, an effect that depends on the α9 cytoplasmic domain. α4β1 enhances migration through reversible binding to the adapter protein, paxillin, but α9β1-dependent migration is paxillin independent. Using yeast two-hybrid screening, we identified the polyamine catabolizing enzyme spermidine/spermine N¹-acetyltransferase (SSAT) as a specific binding partner of the α9 cytoplasmic domain. Overexpression of SSAT increased α9β1-mediated migration, and small interfering RNA knockdown of SSAT inhibited this migration without affecting cell adhesion or migration that was mediated by other integrin cytoplasmic domains. The enzyme activity of SSAT is critical for this effect, because a catalytically inactive version did not enhance migration. We conclude that SSAT directly binds to the α9 cytoplasmic domain and mediates α9-dependent enhancement of cell migration, presumably by localized effects on acetylation of polyamines or of unidentified substrates.

Sheppard, Dean. Functions of Pulmonary Epithelial Integrins: From Development to Disease. Physiol Rev 83: 673–686, 2003; 10.1152/physrev.00033.2002.—Signals from integrins are now known to play critical roles in virtually every aspect of the behavior of epithelial cells, including survival, proliferation, maintenance of polarity, secretory differentiation, and malignant transformation. The cells that line the conducting airways and alveoli of the lung, like most surface epithelia, simultaneously express multiple members of the integrin family, including several with broadly overlapping ligand binding specificities. Although multiple integrins on airway epithelial cells may support adhesion to the same ligands, the functional roles of each integrin that has been examined in detail are quite distinct. Findings from mice expressing null mutations of some of these integrins have identified roles for epithelial cells and epithelial integrins in lung development and in the regulation of lung inflammation, macrophage protease expression, pulmonary fibrosis, and the pulmonary edema that follows acute lung injury. Epithelial integrins are thus attractive targets for intervention in a number of common lung disorders.