CST Guide:
Create successful ePaper yourself
Turn your PDF publications into a flip-book with our unique Google optimized e-Paper software.
Section I: Research Areas<br />
Translational Control: Overview<br />
eEF2K<br />
GTP<br />
eEF1<br />
Cap<br />
Cap<br />
eEF2<br />
GTP<br />
AUG<br />
eEF2 Control:<br />
Ca 2+<br />
cAMP<br />
mTORC1<br />
40S<br />
AUG<br />
60S<br />
eIF5B<br />
GDP<br />
Elongation<br />
40S<br />
60S<br />
Factor<br />
Release<br />
eIF3<br />
A (n)<br />
eIF1A<br />
Nascent<br />
Polypeptide<br />
ER Lumen<br />
Initiation Codon<br />
Recognition<br />
eIF2<br />
GDP<br />
A(n)<br />
eIF5<br />
Cap<br />
eIF1<br />
Polypeptide<br />
Chain<br />
eIF4 Control:<br />
Growth Factors (mTORC1),<br />
Hormones, Cytokines, Mitogens,<br />
Neuropeptides, Oxidative Stress<br />
48S<br />
AUG<br />
Cap<br />
eIF6<br />
eIF5B<br />
GTP<br />
60S<br />
A (n)<br />
Initiation<br />
Stress Granules<br />
P-bodies<br />
40S<br />
Scanning<br />
AAAAA<br />
DHX29<br />
miRNA<br />
60S<br />
48S<br />
Cap<br />
AUG<br />
eIF4B<br />
eRF1<br />
eRF3<br />
GTP<br />
A (n)<br />
ON<br />
eIF4F<br />
Cap<br />
PABP AUG<br />
A (n)<br />
Termination<br />
eIF2 Control:<br />
Viral Infection (dsRNA), (PKR)<br />
Amino Acid Starvation, UV Light (GCN2)<br />
Heme Deficiency (HRI)<br />
Heat Shock, ER Stress, Hypoxia (PERK)<br />
miRNA<br />
43S<br />
eIF2<br />
Met-tRNAi<br />
GTP<br />
eIF3<br />
40S<br />
Initiation<br />
Complex<br />
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<br />
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<br />
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<br />
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<br />
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<br />
a stop codon, eRF1 and eRF3 mediate termination of translation and ribosome disassembly and recycling.<br />
Select Reviews:<br />
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,<br />
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–<br />
10692. • Steitz, T.A. (2008) Nat. Rev. Mol. Cell Biol. 9, 242–253.<br />
eIF1A<br />
eIF1<br />
eIF5<br />
OFF<br />
Translational Control: Regulation of elF4E and p70 S6K<br />
Amino<br />
Acids<br />
GRB10<br />
Hormones, Growth Factors,<br />
Cytokines, Neuropeptides Mitogens Stress<br />
IRS-1<br />
PI3K<br />
RagA/B<br />
RagC/D<br />
4E-<br />
BP1 eIF4E<br />
Translation Off<br />
mTORC1<br />
GβL Raptor<br />
mTOR<br />
DEPTOR<br />
AMP:<br />
ATP<br />
LKB1<br />
AMPK<br />
PIP 3<br />
PDK1<br />
Akt<br />
TSC2<br />
TSC1 TBC1D7<br />
PRAS40 rapamycin<br />
FKBP12<br />
mTORC1<br />
mTORC2<br />
Sin1 PRR5<br />
Rictor GβL<br />
mTOR<br />
DEPTOR<br />
S6<br />
4E-<br />
BP1<br />
chapter 01: GENE EXPRESSION, EPIGENETICS, AND NUCLEAR FUNCTION<br />
PTEN<br />
mTORC2<br />
GSK-3<br />
Torin1<br />
PP242<br />
KU63794<br />
WYE354<br />
p70 S6K<br />
PDCD4<br />
eIF4B<br />
elF4A eIF4H<br />
MNK<br />
eIF4E eIF4G<br />
eIF4F<br />
Cap<br />
PABP<br />
AAAAA<br />
eIF4F<br />
LRP<br />
Wnt<br />
Frizzled<br />
Gα q/o<br />
Dvl<br />
Erk<br />
p90RSK<br />
PABP<br />
PAIP1<br />
PAIP2<br />
43S<br />
48S<br />
p38 MAPK<br />
eEF2K eEF2<br />
Translation Elongation On<br />
Translation On<br />
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<br />
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<br />
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<br />
protein (PABP). Binding of eIF4F to the cap is hindered by eIF4E binding proteins (4EBPs), which, when hypophosphorylated, sequester eIF4E and prevent its association<br />
with eIF4G. However, in response to positive stimuli such as growth factors, mitogens, and amino acids, mTORC1 phosphorylates 4EBPs and relieves this inhibition, allowing<br />
the formation of eIF4F and subsequent initiation of translation. In addition, mTORC1 - alongside PDK1 - phosphorylates S6 kinase, which in turn phosphorylates numerous<br />
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;<br />
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<br />
phosphorylation of eIF4B as well as eIF4E, via MNK kinases.<br />
Select Reviews:<br />
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,<br />
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,<br />
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.<br />
and Meyuhas, O. (2006) Trends Biochem. Sci. 31, 342–348. • Sonenberg, N. and Hinnebusch, A.G. (2009) Cell 136, 731–745.<br />
© 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.<br />
© 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.<br />
36 For Research Use Only. Not For Use in Diagnostic Procedures. See pages 302 & 303 for Pathway Diagrams, Application, and Reactivity keys.<br />
www.cellsignal.com/cstpathways<br />
37