Controlling smad4 signaling with a wip

Members of the transforming growth factor-beta (TGF-beta) family play key roles in embryogenesis and in maintaining tissue homeostasis, and their perturbation can result in a broad range of diseases. One way TGF-beta family signaling pathways are kept in check is by reversible (de)phosphorylation of intracellular Smad effectors. In this issue of EMBO Reports, Park et al [1] identify the phosphatase wild-type p53-induced phosphatase 1 (Wip1) as a negative regulator of TGF-beta family signaling. Mechanistically, Wip1 constrains TGF-beta family signaling through direct dephosphorylation of Thr277, an activating MAP kinase phosphorylation site located in the linker region of the common mediator Smad4.Cancer Signaling networks and Molecular Therapeutic