Loss of p38γ MAPK induces pleiotropic mitotic defects and massive cell death

The p38 mitogen-activated protein kinase (p38 MAPK) family, which is comprised of four protein isoforms, p38 alpha, p38 beta, p38 gamma and p38 delta, forms one of the key MAPK pathways. The p38 MAPKs are implicated in many cellular processes including inflammation, differentiation, cell growth, cell cycle and cell death. The function of p38 MAPKs in mitotic entry has been well established, but their role in mitotic progression has remained controversial. We identify p38 gamma MAPK as a modulator of mitotic progression and mitotic cell death. In HeLa cells, loss of p38 gamma results in multipolar spindle formation and chromosome misalignment, which induce a transient M phase arrest. The majority of p38 gamma-depleted cells die at mitotic arrest or soon after abnormal exit from M-phase. We show that p38 MAPKs are activated at the kinetochores and spindle poles throughout mitosis by kinase(s) that are stably bound to these structures. Finally, p38 gamma is required for the normal kinetochore localization of polo-like kinase 1 (Plk1), and this contributes to the activity of the p38 MAPK pathway. Our data suggest a link between mitotic regulation and the p38 MAPK pathway, in which p38 gamma prevents chromosomal instability and supports mitotic cell viability.