Tumor cells commonly adapt survival strategies by downregulation or mutational inactivation of TGF-beta receptors thereby reversing TGF-beta 1-mediated growth arrest. However, TGF-beta 1-triggered signaling also has a protumor effect through promotion of tumor cell migration. The mechanism(s) through which malignant cells reconcile this conflict by avoiding growth arrest, but strengthening migration remains largely unclear. TGF-beta RII was overexpressed in the bladder cancer cell line T24, concomitant with point mutations, especially the Glu(269) to Lys mutation (G -> A). Whilst leaving Smad2/3 binding unaffected, TGF-beta RII mutations resulted in the unaffected tumor cell growth and also enhanced cell mobility by TGF-beta 1 engagement. Such phenomena are perhaps partially explained by the mutated TGF-beta RII pathway deregulating the p15 and Cdc25A genes that are important to cell proliferation and CUTL1 gene relevant to motility. On the other hand, transfecting recombinant TGF-beta RII-Fc vectors or smad2/3 siRNA blocked such abnormal gene expressions. Clinically, such G -> A mutations were also found in 18 patients (n=46) with bladder cancer. Comparing the clinical and pathologic characteristics, the pathologic T category (chi(2) trend = 7.404, P< 0.01) and tumor grade (chi(2) trend = 9.127, P< 0.01) tended to increase in the G -> A mutated group (TGF-beta RII point-mutated group). These findings provide new insights into how TGF-beta 1 signaling is tailored during tumorigenesis and new information into the current TGF-beta 1-based therapeutic strategies, especially in bladder cancer patient treatment.