An enzyme with self-control

U nlike enzymes that depend on other proteins to rein in their activity, polo-like kinase 4 (Plk4) does the job itself. Holland et al. reveal that Plk4, which helps regulate centro-some duplication, reduces its activity by initiating its own destruction (1). By sacrifi cing itself, the protein prevents cells from building too many centrosomes. Cells prepare to divide by duplicating the centrosome, the organelle that serves as a hub for the cytoskeleton and an anchor for the mitotic spindle. The problem is how to make only one copy before each round of cell division. Extra centrosomes can disrupt chromosome separation during mitosis and might trigger cancer (2), although the evidence for that effect remains controversial. Managing centrosome duplication is the job of Plk4, which prompts the pair of centrioles in the centrosome to replicate. Cells must carefully calibrate Plk4 levels because too much or too little of the enzyme promotes tumors (3, 4). In fruit fl ies, a protein complex called SCF Slimb helps regulate Plk4's abundance by ubiquitinating phospho-rylated copies of the enzyme, spurring their demolition by the proteasome (5). Mammals carry an equivalent to SCF Slimb known as SCF ␤-TrCP , but other aspects of the mechanism that sets Plk4 levels in mammalian cells remain murky. What little Plk4 cells harbor usually disappears rapidly. The enzyme adds phosphates to targets including other Plk4 molecules, suggesting that self-phosphorylation might spur its speedy demise. To test this idea, Hol-land et al. engineered human cells to produce normal Plk4 or a nonfunc-tional variant. The amount of Plk4 was 10 times higher in cells that made the defective enzyme. The researchers also tested a Plk4 version whose phosphory-lation ability could be shut down with a drug called 1NM-PP1. Adding the inhibitor to cells caused the amount of Plk4 to shoot up. The picture that emerges from these experiments, the researchers say, is that in mammalian cells Plk4 molecules stimulate their own breakdown by phosphorylating each other. Whether an individual Plk4 molecule can affix phosphates to itself isn't clear, says first author Andrew Holland, but he thinks it's highly likely that Plk4 is auto-phosphorylating. The team also nailed down where the phosphates attach to Plk4. Previous studies identified two phosphate-ready amino acids within a region of the protein that attracts the ubiquitinating complex SCF ␤-TrCP. Holland et al. replaced these two amino acids with alanines, which can't be phospho-rylated and thus prevent SCF …