(A) PHLPP1 and PHLPP2 are PP2C-type Ser/Thr protein phosphatases, belonging to the protein phosphatase magnesium/manganese (PPM)-dependent shrub of the protein phosphatase phylogenetic tree [115]. (B) Domain structure of ancestral and mammalian PHLPP. Yeast CYR1 contains a Gα domain, 26 Leucine rich repeats (LRR), a PP2C phosphatase domain (PP2C) fused to adenylate cyclase (AC), and C-terminal cyclase-associated protein 1 binding domain (CAP). Mammalian PHLPP retains the LRR domain (18 in PHLPP1 and 19 in PHLPP2) and PP2C phosphatase domain in addition to a PH domain (PH), N-terminal extension (NTE) containing a bipartite Nuclear Localization Signal (NLS), and C-terminal PDZ ligand. Scale bar denotes 100 amino acids (a.a.).