Interactions between various signaling pathways enable a fine control of cellular activities. When the cells are subjected to activation of TGF-β signaling and PKC signaling, PKC phosphorylation of Smad3 abrogates binding and transcriptional activity of Smad3 leading to suppression of TGF-β response. We studied this interaction between Smads and PKC in different cell types to examine cell specificity of the interaction. We found that the outcome of the interaction between Smads and PKC depends on cell types and inducibility of a regulatory molecule Tsc-22. In this report, we showed that induced Tsc-22 leads to enhancement of TGF-β-dependent signaling and the enhancement was blocked by expression of a dominant-negative Tsc-22 mutant. Its effect on cellular differentiation was also examined.