Nek10 mediates G2/M cell cycle arrest and MEK autoactivation in response to UV irradiation.
Appropriate cell cycle checkpoint control is essential for the maintenance of cell and organismal homeostasis. Members of the Nek (NIMA-related kinase) family of serine/threonine protein kinases have been implicated in the regulation of various aspects of the cell cycle. We explored the cellular functions of Nek10, a novel member of the Nek family, and demonstrate a role for Nek10 in the cellular UV response. Nek10 was required for the activation of extracellular signal-regulated kinase 1/2 (ERK1/2) signaling upon UV irradiation but not in response to mitogens, such as epidermal growth factor stimulation. Nek10 physically associated with Raf-1 and MEK1 in a Raf-1-dependent manner, and the formation of this complex was necessary for Nek10-mediated MEK1 activation. Nek10 did not affect the kinase activity of Raf-1 but instead promoted the autophosphorylation-dependent activation of MEK1. The appropriate maintenance of the G(2)/M checkpoint following UV irradiation required Nek10 expression and ERK1/2 activation. Taken together, our results uncover a role for Nek10 in the cellular response to UV irradiation.
Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 2M9, Canada.
Larissa S
LS
Moniz
Vuk
V
Stambolic
D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle / Q000502:physiology* / Q000528:radiation effects*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002455:Cell Division / Q000502:physiology / Q000528:radiation effects; D002460:Cell Line; D045744:Cell Line, Tumor; D003001:Cloning, Molecular; D017931:DNA Primers / Q000235:genetics; D004789:Enzyme Activation / Q000528:radiation effects; D005260:Female; D016195:G2 Phase / Q000502:physiology / Q000528:radiation effects; D055785:Gene Knockdown Techniques; D020022:Genetic Predisposition to Disease; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D009097:Multienzyme Complexes / Q000378:metabolism; D000072380:NIMA-Related Kinase 1; D000072379:NIMA-Related Kinases; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D014466:Ultraviolet Rays / Q000009:adverse effects*
D018797:Cell Cycle Proteins; D017931:DNA Primers; D009097:Multienzyme Complexes; C000606914:NEK1 protein, human; D000072380:NIMA-Related Kinase 1; D000072379:NIMA-Related Kinases; C555351:Nek10 protein, human; D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human