Intracrine signaling mechanisms of activin A and TGF-ß.

While autocrine stimulation of cells by Activin A and/or its family member transforming growth factor ß (TGF-ß) is a phenomenon observed in a variety of cell types, little is known of putative intracellular signaling loops of these cytokines. Intracellular actions of several peptide hormones, growth factors, as well as of extracellular signaling enzymes and DNA-binding proteins, either within target cells or within their cells of synthesis have been shown. Although these intracrine moieties are structurally diverse, they share certain characteristics of synthesis and function. Depending on the cell type, there are reports of stimulatory as well as inhibitory mechanisms induced by such intracrine mechanisms, and this also accounts for transforming growth factor ß (TGF-ß), whereas only stimulatory intracrine signaling of Activin A could be demonstrated so far. Stimulatory intracrine signaling loops of TGF-ß were shown following calpain-dependent intracellular proteolytic activation of the latent cytokine in hepatocytes under cellular stress conditions of this cytokine, leading to transcriptional activation of connective tissue growth factor (CTGF/CCN2) as a representative TGF-ß-sensitive reporter gene. In contrast to TGF-ß, increasing intrahepatocellular concentrations of Activin A are not the result of release from an intracellularly deposited latent complex, but of active de novo synthesis. The stimulatory intracrine signaling pathways of both, TGF-ß and Activin A, are proposed to occur via Alk4/Alk5 receptors and Smad2, whereas additional activation of Smad3 only seems to be involved in intracrine Activin A signaling. However, intracrine TGF-ß signaling may itself also be inhibitory as active TGF-ß is also able to bind to intracellular TGF-ß type II receptor, resulting in a ligand-induced impediment in receptor trafficking to the cell surface. Whether stimulatory or inhibitory modulation of the TGF-ß pathway takes place seems to depend on the cell type and environmental conditions. Future studies are necessary at this point.