Transforming growth factor beta (TGF beta) is a secreted growth and differentiation factor that influences vital cellular processes like proliferation, adhesion, motility, and apoptosis. Regulation... Show moreTransforming growth factor beta (TGF beta) is a secreted growth and differentiation factor that influences vital cellular processes like proliferation, adhesion, motility, and apoptosis. Regulation of the TGF beta signaling pathway is of key importance to maintain tissue homeostasis. Perturbation of this signaling pathway has been implicated in a plethora of diseases, including cancer. The effect of TGF beta is dependent on cellular context, and TGF beta can perform both anti- and pro-oncogenic roles. TGF beta acts by binding to specific cell surface TGF beta type I and type II transmembrane receptors that are endowed with serine/threonine kinase activity. Upon ligand-induced receptor phosphorylation, SMAD proteins and other intracellular effectors become activated and mediate biological responses. The levels, localization, and function of TGF beta signaling mediators, regulators, and effectors are highly dynamic and regulated by a myriad of post-translational modifications. One such crucial modification is ubiquitination. The ubiquitin modification is also a mechanism by which crosstalk with other signaling pathways is achieved. Crucial effector components of the ubiquitination cascade include the very diverse family of E3 ubiquitin ligases. This review summarizes the diverse roles of E3 ligases that act on TGF beta receptor and intracellular signaling components. E3 ligases regulate TGF beta signaling both positively and negatively by regulating degradation of receptors and various signaling intermediates. We also highlight the function of E3 ligases in connection with TGF beta's dual role during tumorigenesis. We conclude with a perspective on the emerging possibility of defining E3 ligases as drug targets and how they may be used to selectively target TGF beta-induced pro-oncogenic responses. Show less
Transforming growth factor (TGF)-beta is a secreted multifunctional cytokine that signals via plasma membrane TGF-beta type I and type II receptors and intercellular SMAD transcriptional effectors.... Show moreTransforming growth factor (TGF)-beta is a secreted multifunctional cytokine that signals via plasma membrane TGF-beta type I and type II receptors and intercellular SMAD transcriptional effectors. Aberrant inter- and intracellular TGF-beta signaling can contribute to cancer progression. In normal cells and early stages of cancer, TGF-beta can stimulate epithelial growth arrest and elicit a tumor suppressor function. However, in late stages of cancer, when the cytostatic effects of TGF-beta in cancer cells are blocked, TGF-beta signaling can act as tumor promoter by its ability to stimulate epithelial-to-mesenchymal transition of cancer cells, by stimulating angiogenesis, and by promoting evasion of immune responses. In this review, we will discuss the rationale and challenges of targeting TGF-beta signaling in cancer and summarize the clinical status of TGF-beta signaling inhibitors that interfere with TGF-beta bioavailability, TGF-beta/receptor interaction, or TGF-beta receptor kinase function. Moreover, we will discuss targeting of TGF-beta signaling modulators and downstream effectors as well as alternative approaches by using promising technologies that may lead to entirely new classes of drugs. Show less
