RESUMEN
SOK1 is a Ste20 protein kinase of the germinal center kinase (GCK) family that has been shown to be activated by oxidant stress and chemical anoxia, a cell culture model of ischemia. More recently, it has been shown to be localized to the Golgi apparatus, where it functions in a signaling pathway required for cell migration and polarization. Herein, we demonstrate that SOK1 regulates cell death after chemical anoxia, as its down-regulation by RNA interference enhances cell survival. Furthermore, expression of SOK1 elicits apoptotic cell death by activating the intrinsic pathway. We also find that a cleaved form of SOK1 translocates from the Golgi to the nucleus after chemical anoxia and that this translocation is dependent on both caspase activity and on amino acids 275-292, located immediately C-terminal to the SOK1 kinase domain. Furthermore, SOK1 entry into the nucleus is important for the cell death response since SOK1 mutants unable to enter the nucleus do not induce cell death. In summary, SOK1 is necessary to induce cell death and can induce death when overexpressed. Furthermore, SOK1 appears to play distinctly different roles in stressed versus non-stressed cells, regulating cell death in the former.
Asunto(s)
Apoptosis/fisiología , Núcleo Celular/metabolismo , Aparato de Golgi/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Transporte Activo de Núcleo Celular/fisiología , Animales , Células COS , Caspasas/fisiología , Hipoxia de la Célula/fisiología , Movimiento Celular/fisiología , Núcleo Celular/genética , Polaridad Celular/fisiología , Supervivencia Celular/fisiología , Chlorocebus aethiops , Aparato de Golgi/genética , Células HeLa , Humanos , Péptidos y Proteínas de Señalización Intracelular , Isquemia/genética , Isquemia/metabolismo , Modelos Biológicos , Mutación , Proteínas Serina-Treonina Quinasas/genética , Estructura Terciaria de Proteína/fisiología , Transducción de Señal/fisiologíaRESUMEN
The Ste20 (sterile 20) proteins are a large family of serine/threonine kinases. Since their discovery a growing body of evidence has implicated them in the regulation of signaling pathways governing cell growth, cell differentiation cell death and cell volume. Approximately 30 human members have been identified based on the high degree of homology of their catalytic domain to that of the Ste20p from Saccharomyces cerevisiae. In addition to the conserved regions, there are also regions of sequence that make each of them unique. In this review we will focus on two subfamilies of the group, GCK-II and GCK-III, families that are closely related but, again, unique in their structural features and biological functions. Herein, we will present what we hope will be the current state of knowledge about these kinases, and discuss what remains to be done in order to better understand their activity and regulation.