The tumor suppressor PTEN is a phosphatase using FAK and Shc as direct substrates, and Akt as a key effector via PIP3. PTEN regulates cell migration and may influence metastases. We quantified PTEN in 135 clear cell renal cell carcinomas (ccRCC) by Western blot analysis and found statistically significant lower PTEN expression in patients who died, usually caused by metastases, within 5 years after surgery, compared to those surviving this time period. In athymic mice, PTEN transfected 786-O cells were injected into the tail vein and metastatic load of the lungs was quantified. We observed a strongly reduced metastatic load after PTEN transfection. For analyses of the PTEN activities, transfections with mutated PTEN genes were performed, leading to loss of lipid phosphatase activity and/or protein phosphatase activity, and of the C-terminal tail. Cell migration was analyzed in a Boyden chamber and phosphorylation of PTEN downstream targets Akt, FAK and Shc by Western blotting. 786-O cells transfected with the functional PTEN gene showed profoundly diminished migration. Transfection with a mutated PTEN isoform leading to loss of protein phosphatase activity, but not of lipid phosphatase activity, abolished this effect. Shc but not FAK seems to mediate this effect. These results show a critical role of PTEN in metastasis of RCC, depending on protein phosphatase activity via Shc. This new insight opens an alley of additional approaches complementing current cancer therapy and metastasis prediction in RCC.