Type I interferon (IFN)-dependent activation of Mnk1 and its role in the generation of growth inhibitory responses.
We provide evidence for the existence of an IFN-regulated cellular pathway involving the mitogen-activated protein kinase (MAPK)-integrating kinase (Mnk) 1. Our data demonstrate that type I (alpha, beta) IFNs induce phosphorylation/activation of Mnk1, which, in turn, regulates phosphorylation of the eukaryotic initiation factor 4E (eIF4E) on Ser-209. Such Mnk activation depends on upstream engagement of Jak1, and requires downstream activation of the Mek/Erk MAPK pathway. In studies using double Mnk1-/-Mnk2-/- knockout mouse embryonic fibroblasts (MEFs), we found that engagement of Mnk kinases is essential for mRNA translation of the Isg15 and Isg54 genes, suggesting an important role for this pathway in mRNA translation of IFN-stimulated genes (ISGs). Importantly, our data demonstrate that pharmacological inhibition of Mnk kinases or siRNA-mediated knockdown of Mnk1 and Mnk2 results in partial reversal of the suppressive effects of IFNalpha on normal and leukemic hematopoietic progenitors, establishing a key role for this pathway in the generation of the growth inhibitory effects of type I IFNs. Together, our findings establish that the Mnk/eIF4E kinase pathway is activated in an IFN-inducible manner and plays important roles in mRNA translation for ISGs and generation of IFN-inducible anti-proliferative responses.
Joshi
Sonali
S
Robert H. Lurie Comprehensive Cancer Center and Division of Hematology- Oncology, Northwestern University Medical School, and Jesse Brown Veterans Administration Medical Center, Chicago, IL 60611, USA.
Kaur
Surinder
S
Redig
Amanda J
AJ
Goldsborough
Katy
K
David
Kevin
K
Ueda
Takeshi
T
Watanabe-Fukunaga
Rie
R
Baker
Darren P
DP
Fish
Eleanor N
EN
Fukunaga
Rikiro
R
Platanias
Leonidas C
LC
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D053613:Janus Kinase 1 / Q000378:metabolism; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D014176:Protein Biosynthesis / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014452:Ubiquitins / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D016207:Cytokines; D039561:Eukaryotic Initiation Factor-4E; C489550:G1p2 protein, mouse; D016898:Interferon-alpha; D012333:RNA, Messenger; D014452:Ubiquitins; C106281:Mknk1 protein, mouse; C106282:Mknk2 protein, mouse; D053613:Janus Kinase 1; D017346:Protein Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases