The laforin–malin complex is able to promote ubiquitination of individual AMPK subunits. (A) Diagram of the protocol used to determine the presence of ubiquitinated proteins, based on the use of a 6xHis-tagged version of ubiquitin (Kaiser and Tagwerker, 2005). (B) HEK293 cells were transfected with plasmid pCMV-His6xUbiq and the indicated combination of plasmids (pLaforin, pCMV-HA-laforin; and pMalin, pcDNA3-HA-malin). Cell extracts were then obtained as described in Materials and Methods and the clarified extract (CE; 40 μg), and the material bound to the metal-affinity chromatography column (bound; 40 μl) was analyzed by SDS-PAGE and Western blotting using anti-myc antibodies. Molecular mass markers are indicated on the left of each panel. For AMPKα2 and AMPKγ1, we also detected a minor modification when only laforin was overexpressed, perhaps because it can force endogenous malin to carry out the corresponding ubiquitination. (C) HEK293 cells were transfected with plasmid pCMV-His6xUbiq and the indicated combination of plasmids (Mdm2, pCMV-Mdm2; Laf/Mal, pCMV-HA-laforin/pcDNA3-HA-malin; and empty, pCMV-HA). Cell extracts were analyzed as described above using anti-myc antibodies. (D) HEK293 cells were transfected with plasmid pCMV-His6xUbiq and plasmids pCMV-p53 and pCMV-Mdm2 or pCMV-HA (empty). Cell extracts were analyzed as described above using anti-p53 antibodies.