Eukaryotic translation initiation factor 3, subunit a, regulates the extracellular signal-regulated kinase pathway.
The extracellular signal-regulated kinase (ERK) pathway participates in the control of numerous cellular processes, including cell proliferation. Since its activation kinetics are critical for to its biological effects, they are tightly regulated. We report that the protein translation factor, eukaryotic translation initiation factor 3, subunit a (eIF3a), binds to SHC and Raf-1, two components of the ERK pathway. The interaction of eIF3a with Raf-1 is increased by β-arrestin2 expression and transiently decreased by epidermal growth factor (EGF) stimulation in a concentration-dependent manner. The EGF-induced decrease in Raf-1-eIF3a association kinetically correlates with the time course of ERK activation. eIF3a interferes with Raf-1 activation and eIF3a downregulation by small interfering RNA enhances ERK activation, early gene expression, DNA synthesis, expression of neuronal differentiation markers in PC12 cells, and Ras-induced focus formation in NIH 3T3 cells. Thus, eIF3a is a negative modulator of ERK pathway activation and its biological effects.
Institute of Neuroscience and Psychology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.
Tian-Rui
TR
Xu
Rui-Fang
RF
Lu
David
D
Romano
Andrew
A
Pitt
Miles D
MD
Houslay
Graeme
G
Milligan
Walter
W
Kolch
D000818:Animals; D019390:Arrestins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D004815:Epidermal Growth Factor / Q000378:metabolism; D039621:Eukaryotic Initiation Factor-3 / Q000235:genetics / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D041681:NIH 3T3 Cells; D016716:PC12 Cells; D011485:Protein Binding; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D051381:Rats; D000071557:beta-Arrestins
D019390:Arrestins; D039621:Eukaryotic Initiation Factor-3; D000071557:beta-Arrestins; D004815:Epidermal Growth Factor; D019908:Proto-Oncogene Proteins c-raf; D048049:Extracellular Signal-Regulated MAP Kinases