Although our previous studies showed that RBX2/SAG, the classical RING component of CRL5 as well as CRL1 promotes NF1 ubiquitylation and degradation to regulate vascular and neural development during embryogenesis,[24] and RBX2/SAG couples with FBXW7 to degrade SHOC2 and regulate KrasG12D‐induced pancreatic tumorigenesis,[25] this is the first study to show directly that FBXW7 could couple with CUL5 for targeted degradation of a FBXW7 substrate, namely RPAP2 under a special condition such as HSP90 inactivation. The gene discussed is SHOC2; the disease is pancreatitis.