Figure 3.

Proposed mechanism of action of Pak1ip1 in both wild-type and homozygous manta-ray mutants. In the wild-type (left) Pak1ip1 acts as an inhibitor of the E3 ubiquitin ligase Mdm2, which acts as an inhibitor of Tp53 activity through an auto-regulatory feedback loop. Mdm2 targets Tp53 for degradation by the proteasome, blocks its transcriptional activity, and facilitates its export from the nucleus. Low levels of Tp53 activity promote cell cycle progression at the G1 checkpoint and cellular proliferation. In the manta-ray mutant (right) Pak1ip1 causes altered 60S ribosome biogenesis, resulting in nucleolar stress and the accumulation of freely circulating ribosomal proteins L5 and L11, which inhibit Mdm2 activity. This series of events leads to an increase in Tp53 levels, G1 cell cycle arrest, and subsequent cell death, which appears to particularly affect aspects of the cranial neural crest.