Translational Control / Regulation of eIf2

Pathway Description:

The eIF2 initiation complex integrates a diverse array of stress-related signals to regulate both global and specific mRNA translation. Under permissive conditions, eIF2 binds GTP and Met-tRNAi to form the ternary complex (TC), which then associates with the 40S ribosomal subunit, eIF1, eIF1A, eIF5, and eIF3 to form the 43S pre-initiation complex (PIC). The 43S PIC scans the mRNA UTR for an AUG start codon. Upon AUG recognition, eIF2 hydrolyzes GTP to GDP with the help of the GTPase activating protein eIF5 and dissociates from the mRNA, permitting the binding of the 60S ribosomal subunit and elongation of the polypeptide chain. eIF2 remains bound to GDP in the presence of eIF5 acting as a GDI. To permit another round of initiation, eIF2B must act as both a GDI displacement factor (GDF) and a guanine exchange factor (GEF) to allow exchange of GDP for GTP on eIF2. This step is tightly regulated, and phosphorylation of eIF2α by a diverse family of four stress activated kinases—PKR (dsRNA), PERK (ER stress), GCN2 (amino acid starvation), and HRI (heme deficiency)—prevents nucleotide exchange by causing eIF2 to act as a dominant negative complex to sequester eIF2B. The resulting increase in eIF2α-GDP limits the availability of the ternary complex and causes a decrease in global protein synthesis and an enhancement of the translation of specific stressrelated mRNA transcripts, such as the transcription factors ATF-4 and CHOP.

Selected Reviews:

Hinnebusch AG (2011) Molecular mechanism of scanning and start codon selection in eukaryotes. Microbiol. Mol. Biol. Rev. 75(3), 434–67, first page of table of contents.

Raven JF, Koromilas AE (2008) PERK and PKR: old kinases learn new tricks. Cell Cycle 7(9), 1146–50.

Schmitt E, Naveau M, Mechulam Y (2010) Eukaryotic and archaeal translation initiation factor 2: a heterotrimeric tRNA carrier. FEBS Lett. 584(2), 405–12.

Stolboushkina EA, Garber MB (2011) Eukaryotic type translation initiation factor 2: structure-functional aspects. Biochemistry Mosc. 76(3), 283–94.

Wek RC, Jiang HY, Anthony TG (2006) Coping with stress: eIF2 kinases and translational control. Biochem. Soc. Trans. 34(Pt 1), 7–11.

We would like to thank Rachel Wolfson and Prof. David Sabatini, Whitehead Institute for Biomedical Research, MIT, Cambridge, MA, for reviewing this diagram.

created January 2002 revised June 2014

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Overview of Calcium, cAmp, and Lipid Signaling

Calcium, cAMP and Lipid Signaling

Protein kinase C (PKC) family members regulate numerous cellular responses including secretion, gene expression, cell proliferation, and the inflammation response. Basic protein structure includes an amino-terminal regulatory region connected to a carboxy-terminal kinase domain by a hinge region. PKC enzymes contain an auto-inhibitory pseudosubstrate domain that binds a catalytic domain sequence to inhibit kinase activity. Binding of second messenger activators localizes PKC enzymes to the cell membrane where allosteric changes allow pseudosubstrate release from the catalytic sequence. Differences among PKC regulatory regions allow for variable second messenger binding and are the basis for the division of the PKC family into 3 broad groups. Conventional PKC enzymes (cPKC; isoforms PKCα, PKCβ, and PKCγ) contain functional C1 and C2 regulatory domains; cPKC enzyme activation requires binding of diacylglycerol (DAG) and a phospholipid to the C1 domain, and Ca2+ binding to the C2 domain. Novel PKC enzymes (nPKC; isoforms PKCδ, PKCε, PKCη, and PKCθ) also require DAG binding for activation but contain a novel C2 domain that does not act as a Ca2+ sensor. Distantly related protein kinase D proteins are often associated with novel PKC enzymes as they respond to DAG but not Ca2+ stimulation. Atypical enzymes (aPKC; isoforms PKCζ and PKCι/λ) contain a non-functional C1 domain and lack a C2 domain, requiring no second messenger binding for aPKC activation.

Activation of PKC enzymes requires a series of phosphorylation events, association with additional proteins, and allosteric changes. All isoforms require phosphorylation at conserved sites within the catalytic domain active loop and turn motifs; conventional and novel enzymes require the additional phosphorylation of a site within a catalytic region hydrophobic motif. Following translation, nascent PKC localizes to the cell membrane where it associates with Hsp90 and Cdc37. Binding of these co-chaperones to the kinase domain precedes phosphorylation of the active loop site by PDK1. Second messengers activate PKC by recruiting the cytosolic enzyme to the plasma membrane where allosteric changes release the pseudosubstrate from the catalytic domain sequence.

Additional phosphorylation events regulate PKC activity by controlling protein interaction, stability, and localization. For example, stimulus-specific phosphorylation of PKCδ can result in PKCδ degradation, cleavage, or increased activity. In response to DNA damage and oxidative stress, PKCδ promotes apoptosis through activation of the p53-mediated pathway and inhibition of prosurvival proteins such as Akt, Cdk1, and cyclin D1. Transduction through the TNF pathway promotes a pro-survival response as PKCδ activates the Akt, NF-κB, and MEK pathways.

References

Newton AC (2010) Protein kinase C: poised to signal. Am. J. Physiol. Endocrinol. Metab. 298(3), E395–402.

Newton PM, Messing RO (2010) The substrates and binding partners of protein kinase Cepsilon. Biochem. J. 427(2), 189–96.

Freeley M, Kelleher D, Long A (2011) Regulation of Protein Kinase C function by phosphorylation on conserved and non-conserved sites. Cell. Signal. 23(5), 753–62.

Basu A, Pal D (2010) Two faces of protein kinase Cδ: the contrasting roles of PKCδ in cell survival and cell death. ScientificWorldJournal 10, 2272–84.

Rozengurt E (2011) Protein kinase D signaling: multiple biological functions in health and disease. Physiology (Bethesda) 26(1), 23–33.

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