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During the late stage of cancer, TGF-β signaling pathway often enforces tumor metastatic behavior, by its immune tolerance function and its capacity to drive the epithelial-mesenchymal transition of tumor cells.It has also been known that the activity of TGF-β/Smad pathway is often elaborately regulated by elements from tumor microenvironment.Screening the human kinome, which often functions as effectors of extracellular cue, we have identified a few kinases which directly phosphorylated the classical-SSXS motif at C-terminus of R-Smads.Similar as receptor-induced phosphorylation, it activated R-Smad, drive the formation of core Smad complex, and facilitated the Smad-dependent transcription.Intriguingly, this is a process independent on the activity or expression of TGF-β receptors.Consequently, stress extracellular cues may directly activate Smad pathway,induce the Smad-responsive expressions, and regulate the epithelial-mesenchymal transition behavior through Smad pathway.In contrast, silencing of their expression may dampen Smad pathway, and impair the epithelial-mesenchymal transition phenotype.We therefore present a novel mode for regulation of Smad signaling by the environmental cues, and provide the evidence for receptor-independent Smad activation.