SMAD-oncoprotein interplay: Potential determining factors in targeted therapies

The Transforming Growth Factor-β (TGF-β) signaling pathway plays a versatile role in diverse physiological and disease conditions. Outcomes of TGF-β signaling are divergent, sometimes even opposite, on cellular functions and disease progression through context-dependent transcriptional programs. For example, TGF-β signaling is well known for its dichotomous roles in cancer progression, serving both as an inhibitor of tumor cell growth and an inducer of tumor metastasis. This is achieved mainly through the interplay between Smad proteins (Smads) and cofactors/modulators in a context-determined manner. Smad proteins can be post-translationally modified through several mechanisms, and are able to interact with many transcription coactivators/corepressors during a wide range of biological functions. As of such, Smads influence on many oncogenic processes through the interplay with proteins in oncogenic pathways. Because of the importance of the TGF-β pathway in cancer progression, the interplay between Smads and oncogenic drug targets has considerable impact on the outcome of targeted therapies. In this review, we focus on the interplay between Smads and oncogenic drug targets, with a discussion on how this interplay guides targeted anticancer therapies.