SAPK pathways and p53 cooperatively regulatePLK4 activity and centrosome integrityunder stress

摘要

Polo-like kinase 4 is essential for centrosome duplication, but its hyperactivation causessupernumerary centrosomes. Here we report that polo-like kinase 4 is directly phosphorylatedand activated by stress-activated protein kinase kinase kinases (SAPKKKs).Stress-induced polo-like kinase 4 activation promotes centrosome duplication, whereasstress-induced SAPK activation prevents centrosome duplication. In the early phase of stressresponse, the balance of these opposing signals prevents centrosome overduplication.However, in the late phase of stress response, p53 downregulates polo-like kinase 4expression, thereby preventing sustained polo-like kinase 4 activity and centrosomeamplification. If both p53 and the SAPKK MKK4 are simultaneously inactivated, as isfrequently found in cancer cells, persistent polo-like kinase 4 activity combined with the lackof SAPK-mediated inhibition of centrosome duplication conspire to induce supernumerarycentrosomes under stress. Indeed, tumour-derived MKK4 mutants induced centrosomeamplification under genotoxic stress, but only in p53-negative cells. Thus, our results reveala mechanism that preserves the numeral integrity of centrosomes, and an unexploredtumour-suppressive function of MKK4.