CST Guide:

Section I: Research Areas
Translational Control: Overview
eEF2K
GTP
eEF1
Cap
Cap
eEF2
GTP
AUG
eEF2 Control:
Ca 2+
cAMP
mTORC1
40S
AUG
60S
eIF5B
GDP
Elongation
40S
60S
Factor
Release
eIF3
A (n)
eIF1A
Nascent
Polypeptide
ER Lumen
Initiation Codon
Recognition
eIF2
GDP
A(n)
eIF5
Cap
eIF1
Polypeptide
Chain
eIF4 Control:
Growth Factors (mTORC1),
Hormones, Cytokines, Mitogens,
Neuropeptides, Oxidative Stress
48S
AUG
Cap
eIF6
eIF5B
GTP
60S
A (n)
Initiation
Stress Granules
P-bodies
40S
Scanning
AAAAA
DHX29
miRNA
60S
48S
Cap
AUG
eIF4B
eRF1
eRF3
GTP
A (n)
ON
eIF4F
Cap
PABP AUG
A (n)
Termination
eIF2 Control:
Viral Infection (dsRNA), (PKR)
Amino Acid Starvation, UV Light (GCN2)
Heme Deficiency (HRI)
Heat Shock, ER Stress, Hypoxia (PERK)
miRNA
43S
eIF2
Met-tRNAi
GTP
eIF3
40S
Initiation
Complex
The synthesis of new proteins is a highly regulated process that allows rapid cellular responses to diverse stimuli at the post-transcriptional level. Nine key eukaryotic translation
initiation factors (eIFs) catalyze the assembly of a functional ribosomal complex in two steps - first, the formation of the 48S complex from the 43S initiation complex
and mRNA followed by its subsequent joining with the 60S subunit, enabling polypeptide chain formation. Of the many steps in translation, the rate-limiting step, initiation, is
subjected to the most regulatory control. Many stimuli, such as growth factors and stress, either stimulate or inhibit specific eIFs. Aside from initiation, translation can also be
attenuated during elongation. For instance, elevated levels of Ca 2+ or cAMP can block the action of eukaryotic elongation factor 2 (eEF2) via AMPK. Finally, upon recognition of
a stop codon, eRF1 and eRF3 mediate termination of translation and ribosome disassembly and recycling.
Select Reviews:
Dever, T.E. and Green, R. (2012) Cold Spring Harb. Perspect. Biol. 4, a013706. • Gebauer, F., and Hentze, M.W. (2004) Nat. Rev. Mol. Cell Biol. 5, 827–835. • Hinnebusch,
A.G. (2011) Microbiol. Mol. Biol. Rev. 75, 434–467. • Sonenberg, N. and Hinnebusch, A.G. (2009) Cell 136, 731–745. • Spirin, A.S. (2009) Biochemistry 48, 10688–
10692. • Steitz, T.A. (2008) Nat. Rev. Mol. Cell Biol. 9, 242–253.
eIF1A
eIF1
eIF5
OFF
Translational Control: Regulation of elF4E and p70 S6K
Amino
Acids
GRB10
Hormones, Growth Factors,
Cytokines, Neuropeptides Mitogens Stress
IRS-1
PI3K
RagA/B
RagC/D
4E-
BP1 eIF4E
Translation Off
mTORC1
GβL Raptor
mTOR
DEPTOR
AMP:
ATP
LKB1
AMPK
PIP 3
PDK1
Akt
TSC2
TSC1 TBC1D7
PRAS40 rapamycin
FKBP12
mTORC1
mTORC2
Sin1 PRR5
Rictor GβL
mTOR
DEPTOR
S6
4E-
BP1
chapter 01: GENE EXPRESSION, EPIGENETICS, AND NUCLEAR FUNCTION
PTEN
mTORC2
GSK-3
Torin1
PP242
KU63794
WYE354
p70 S6K
PDCD4
eIF4B
elF4A eIF4H
MNK
eIF4E eIF4G
eIF4F
Cap
PABP
AAAAA
eIF4F
LRP
Wnt
Frizzled
Gα q/o
Dvl
Erk
p90RSK
PABP
PAIP1
PAIP2
43S
48S
p38 MAPK
eEF2K eEF2
Translation Elongation On
Translation On
Translation is a tightly regulated process, and the mTORC1-S6K signaling axis plays a critical role in this control. The rate of translation initiation is predominantly determined
by 5’ cap recognition by eIF4F, a trimeric protein complex composed of eIF4E, which binds the 5ʹ cap; eIF4A, a helicase necessary for unwinding complex secondary structure
in the leader sequence; and eIF4G, a large scaffolding protein that delivers the mRNA to eIF3 and mediates mRNA circularization through association with polyA binding
protein (PABP). Binding of eIF4F to the cap is hindered by eIF4E binding proteins (4EBPs), which, when hypophosphorylated, sequester eIF4E and prevent its association
with eIF4G. However, in response to positive stimuli such as growth factors, mitogens, and amino acids, mTORC1 phosphorylates 4EBPs and relieves this inhibition, allowing
the formation of eIF4F and subsequent initiation of translation. In addition, mTORC1 - alongside PDK1 - phosphorylates S6 kinase, which in turn phosphorylates numerous
substrates involved in translation. These include S6 small ribosomal subunit; eIF4B, an activator of the eIF4A helicase; PDCD4, an eIF4A inhibitor that is inhibited by phosphorylation;
and SKAR, an mRNA splicing factor. Aside from the mTORC1 pathway, the Ras-MAPK pathway is another major regulator of translation and is responsible for the
phosphorylation of eIF4B as well as eIF4E, via MNK kinases.
Select Reviews:
Dowling, R.J., Topisirovic, I., Fonseca, B.D., and Sonenberg, N. (2010) Biophys. Acta. 1804, 433–439. • Fenton T.R. and Gout, I.T. (2011) Int. J. Biochem. Cell Biol. 43,
47–59. • Graff, J.R., Konicek, B.W., Carter, J.H., and Marcusson, E.G. (2008) Cancer Res. 68, 631–634. • Holcik, M. and Sonenberg, N. (2005) Nat. Rev. Mol. Cell Biol. 6,
318–327. • Huang, J. and Manning, B.D. (2008) Biochem. J. 412, 179–190. • Magnuson, B., Ekim, B., and Fingar, D.C. (2012) Biochem. J. 441, 1–21. • Ruvinsky, I.
and Meyuhas, O. (2006) Trends Biochem. Sci. 31, 342–348. • Sonenberg, N. and Hinnebusch, A.G. (2009) Cell 136, 731–745.
© 2002–2015 Cell Signaling Technology, Inc. • We would like to thank Rachel Wolfson and Prof. David Sabatini, Whitehead Institute for Biomedical Research, MIT, Cambridge, MA, for reviewing this diagram.
© 2002–2015 Cell Signaling Technology, Inc. • We would like to thank Rachel Wolfson and Prof. David Sabatini, Whitehead Institute for Biomedical Research, MIT, Cambridge, MA, for reviewing this diagram.
36 For Research Use Only. Not For Use in Diagnostic Procedures. See pages 302 & 303 for Pathway Diagrams, Application, and Reactivity keys.
www.cellsignal.com/cstpathways
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