SMAD4 and nonpapillary renal cell carcinoma: Secondly, given that AMPK is a kinase of diverse targets and the TGF-β/SMAD pathway engages in a reciprocal cross talk with various molecules [7,21], it is readily assumable that pAMPK might activate and cooperate with pSMAD2/SMAD4 to downregulate ccRCC, either directly or indirectly by way of modulating other pathways.