TI - Conclusions . AB - The studies presented here revealed a physical link between a key signal transducer of TGF-beta (Smad3) and a component ( APC10 ) of the cell cycle regulatory E3 ligase APC , and further suggest a molecular mechanism via which such a physical interaction contributes to the regulation of the protein stability of a multi domain cytoplasmic docking protein HEF1 , which is involved in a large network of signaling events . Since Smad3 interacts with many other nuclear and cytoplasmic proteins , this observation may have broad implications for the regulation of these other Smad3 interactors in a similar fashion . While previous studies of the APC complex have been primarily limited to cell cycle control , the observations reported recently extended the role of APC into non cell cycle events associated with SnoN [18,19] . Our studies here provide the detailed link between Smad3 and APC and now add a cytoplasmic signaling adapter onto the list of APC SUBstrates . The data imply that the cellular functions previously viewed as separate are intimately interwoven in a complex fashion : a cell cycle regulatory E3 ligase is physically and functionally connected to the vast signaling networks involving Smad3 and HEF1 . Furthermore the biological consequences of the TGF-beta -induced HEF1 degradation in lymphocytes where HEF1 is predominantly expressed have yet to be studied and their understanding could lead to new insights in the molecular events involved in the onset of complex diseases such as cancers .