SMAD3 and neoplasm: The surprising discovery of RAC1B being able to induce both SMAD3 [13] and SMAD4 [85] protein expression can be interpreted as an attempt to compensate for the loss of Smad activation by activated ALK5 to ensure execution of tumor-suppressive functions such as growth arrest and apoptosis, despite low levels of ALK5 and/or exogenous TGFβ that reaches the receptors on the cell surface (Figure 4, left-hand side).