The role of Beta-arrestins in respiratory pathophysiology and tumorigenesis: going a step beyond the cell surface.

Beta-arrestins are small cytosolic proteins that have been known so far as negative feedback regulators of G-protein coupled receptors (GPCRs). This receptor superfamily, characterized by a heptahelical transmembrane motif, mediates the signals of a multitude of extracellular ligands including chemokines, cytokines, hormones and growth factors. Beta-arrestins "arrest" the GPCR signaling capability through its desensitization and internalization. However, novel roles for these molecules have emerged and research demonstrates that beta-arrestins can mediate intracellular signaling independently of their effects on G-protein stimulation. Acting as scaffolding proteins, they can lead to the assembly of intracellular signalsomes that can activate or inhibit the function of various signaling cascades, such as the MAP kinase, JNK and NF-kappaB cascades, ultimately affecting gene expression. Finally, they can even regulate gene transcription by modulating histone acetylation and chromatin assembly. This pleiotropic activity of beta-arrestins can regulate both physiologic and pathophysiologic responses and will be reviewed in the context of lung inflammatory diseases and lung cancer.