The abnormalities of transforming growth factor-β (TGF-β)/Smad signaling are correlated with many human diseases including cancers and cardiovascular diseases.To investigate the physiological functions and mechanisms of TGF-β/Smad signaling in the maintenance of tissue homeostasis, we disrupted the cellular responses to TGF-β signals by generating various tissue specific Smad4 gene knockout mice using the Cre-LoxP system.We found that TGF-β/Smad4 signaling inhibits the overactivation of tissue stem cell and cell proliferation,maintains the homeostasis of differentiated cells, stabilizes cerebrovascular endothelial cell-pericyte interactions.Our resultshave demonstrated the causative link between the impaired TGF-β/Smad signaling and various diseases, including skin and esophageal squamous cell carcinoma, cardiac hypertrophy, intracranial hemorrhage.Very recently, we investigated the synergetic effect between Smad4 and PTEN on suppressing gastric tumor initiation.