TGF-beta signaling: a tale of two responses.
Transforming growth factor-beta (TGF-beta) regulates a wide variety of cellular processes including cell growth, apoptosis, differentiation, migration, and extracellular matrix production among others. The canonical signaling pathway induced by the TGF-beta receptor complex involves the phosphorylation of Smad proteins which upon activation accumulate in the nucleus and regulate transcription. Interestingly, the cellular response to TGF-beta can be extremely variable depending on the cell type and stimulation context. TGF-beta causes epithelial cells to undergo growth arrest and apoptosis, responses which are critical to suppressing carcinogenesis, whereas it can also induce epithelial-mesenchymal transition and mediate fibroblast activation, responses implicated in promoting carcinogenesis and fibrotic diseases. However, TGF-beta induces all these responses via the same receptor complex and Smad proteins. To address this apparent paradox, during the last few years a number of additional signaling pathways have been identified which potentially regulate the different cellular responses to TGF-beta. The identification of these signaling pathways has shed light onto the mechanisms whereby Smad and non-Smad pathways collaborate to induce a particular cellular phenotype. In this article, we review TGF-beta signaling in epithelial cells and fibroblasts with a focus on understanding the mechanisms of TGF-beta versatility.
Rahimi
Rod A
RA
Department of Biochemistry and Molecular Biology, Thoracic Diseases Research Unit, Mayo Clinic Cancer Center, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
Leof
Edward B
EB
D000818:Animals; D017209:Apoptosis; D001671:Biochemistry / Q000379:methods; D004789:Enzyme Activation; D004848:Epithelium / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D008648:Mesoderm / Q000378:metabolism; D008954:Models, Biological; D009857:Oncogenes; D010641:Phenotype; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D051785:Smad Proteins; D016212:Transforming Growth Factor beta