Transforming growth factor-β signaling and ubiquitinators in cancer

Transforming growth factor-β (TGF-β) represents a large family of growth and differentiation factors that mobilize complex signaling networks to regulate cellular differentiation, proliferation, motility, adhesion, and apoptosis. TGF-β signaling is tightly regulated by multiple complex mechanisms, and its deregulation plays a key role in the progression of many forms of cancer. Upon ligand binding, TGF-β signals are transduced by Smad proteins, which in turn are tightly dependent on modulation by adaptor proteins such as embryonic liver fodrin, Smad anchor for receptor activation, filamin, and crkl. A further layer of regulation is imposed by ubiquitin-mediated targeting and proteasomal degradation of specific components of the TGF-β signaling pathway. This review focuses on the ubiquitinators that regulate TGF-β signaling and the association of these ubiquitin ligases with various forms of cancer. Delineating the role of ubiquitinators in the TGF-β signaling pathway could yield powerful novel therapeutic targets for designing new cancer treatments.