MNK1-induced eIF-4E phosphorylation in myeloma cells: a pathway mediating IL-6-induced expansion and expression of genes involved in metabolic and proteotoxic responses.
Because multiple myeloma (MM) cells are at risk for endoplasmic reticulum (ER) stress, they require a carefully regulated mechanism to promote protein translation of selected transcripts when proliferation is stimulated. MAPK-interacting kinases (MNKs) may provide this mechanism by enhancing cap-dependent translation of a small number of critical transcripts. We, thus, tested whether MNKs played a role in MM responses to the myeloma growth factor interleukin-6 (IL-6). IL-6 activated MNK1 phosphorylation and induced phosphorylation of its substrate, eIF-4E, in MM lines and primary specimens. MNK paralysis, achieved pharmacologically or by shRNA, prevented MM expansion stimulated by IL-6. A phosphodefective eIF-4E mutant also prevented the IL-6 response, supporting the notion that MNK's role was via phosphorylation of eIF-4E. Both pharmacological MNK inhibition and expression of the phosphodefective eIF-4E mutant inhibited MM growth in mice. Although critical for IL-6-induced expansion, eIF-4E phosphorylation had no significant effect on global translation or Ig expression. Deep sequencing of ribosome-protected mRNAs revealed a repertoire of genes involved in metabolic processes and ER stress modulation whose translation was regulated by eIF-4E phosphorylation. These data indicate MM cells exploit the MNK/eIF-4E pathway for selective mRNA translation without enhancing global translation and risking ER stress.
Department of Medicine, Hematology-Oncology, Greater Los Angeles VA Healthcare Center, Los Angeles, California, United States of America; Department of Medicine, UCLA School of Medicine, Los Angeles, California, United States of America; Jonsson Comprehensive Cancer Center, Los Angeles, California, United States of America.
Yijiang
Y
Shi
Department of Medicine, Hematology-Oncology, Greater Los Angeles VA Healthcare Center, Los Angeles, California, United States of America; Department of Medicine, UCLA School of Medicine, Los Angeles, California, United States of America; Jonsson Comprehensive Cancer Center, Los Angeles, California, United States of America.
Patrick
P
Frost
Department of Medicine, Hematology-Oncology, Greater Los Angeles VA Healthcare Center, Los Angeles, California, United States of America; Department of Medicine, UCLA School of Medicine, Los Angeles, California, United States of America; Jonsson Comprehensive Cancer Center, Los Angeles, California, United States of America.
Bao
B
Hoang
Department of Medicine, Hematology-Oncology, Greater Los Angeles VA Healthcare Center, Los Angeles, California, United States of America; Department of Medicine, UCLA School of Medicine, Los Angeles, California, United States of America; Jonsson Comprehensive Cancer Center, Los Angeles, California, United States of America.
Yonghui
Y
Yang
Department of Medicine, Hematology-Oncology, Greater Los Angeles VA Healthcare Center, Los Angeles, California, United States of America; Department of Medicine, UCLA School of Medicine, Los Angeles, California, United States of America; Jonsson Comprehensive Cancer Center, Los Angeles, California, United States of America.
Carolyne
C
Bardeleben
Department of Medicine, Hematology-Oncology, Greater Los Angeles VA Healthcare Center, Los Angeles, California, United States of America; Department of Medicine, UCLA School of Medicine, Los Angeles, California, United States of America; Jonsson Comprehensive Cancer Center, Los Angeles, California, United States of America.
Joseph
J
Gera
Department of Medicine, Hematology-Oncology, Greater Los Angeles VA Healthcare Center, Los Angeles, California, United States of America; Department of Medicine, UCLA School of Medicine, Los Angeles, California, United States of America; Jonsson Comprehensive Cancer Center, Los Angeles, California, United States of America.
Alan
A
Lichtenstein
D000818:Animals; D045744:Cell Line, Tumor; D059865:Endoplasmic Reticulum Stress; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism*; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D009101:Multiple Myeloma / Q000378:metabolism*; D010766:Phosphorylation; D014176:Protein Biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*
D039561:Eukaryotic Initiation Factor-4E; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; C491395:MKNK1 protein, human; D017346:Protein Serine-Threonine Kinases