Eukaryotic translation initiation factor 4E-binding protein 1 (also known as 4E-BP1) is a protein that in humans is encoded by the EIF4EBP1 gene. [5] inhibits cap-dependent translation by binding to translation initiation factor eIF4E. Phosphorylation of 4E-BP1 results in its release from eIF4E, thereby allows cap-dependent translation to continue thereby increasing the rate of protein synthesis. [6]
Phosphorylated 4E-BP1 is thought to be a marker of upstream signaling (mTOR) activation. 4E-BP1 has seven phospho-sites, the three most important of which are the initiation site Thr 37/Thr 46, the second site Thr 70, and the final site Ser65. Moreover, phosphorylation of Ser 65 and Thr 70 alone was not sufficient to block the inhibition of mRNA translation by 4E-BP1, suggesting that multiple phosphorylation events must be combined to increase the rate of protein synthesis. [7]
This gene encodes one member of a family of translation repressor proteins. The protein directly interacts with eukaryotic translation initiation factor 4E (eIF4E), which is a limiting component of the multisubunit complex that recruits 40S ribosomal subunits to the 5' end of mRNAs. Interaction of this protein with eIF4E inhibits complex assembly and represses translation. This protein is phosphorylated in response to various signals including UV irradiation and insulin signaling, resulting in its dissociation from eIF4E and activation of cap-dependent mRNA translation. [8]
High level of phosphorylated 4E-BP1 has been widely reported in human cancers, and is associated with a worse outcome in several malignancies. [9]
EIF4EBP1 has been shown to interact with:
The mammalian target of rapamycin (mTOR), also referred to as the mechanistic target of rapamycin, and sometimes called FK506-binding protein 12-rapamycin-associated protein 1 (FRAP1), is a kinase that in humans is encoded by the MTOR gene. mTOR is a member of the phosphatidylinositol 3-kinase-related kinase family of protein kinases.
4EGI-1 is a synthetic chemical compound which has been found to interfere with the growth of certain types of cancer cells in vitro. Its mechanism of action involves interruption of the binding of cellular initiation factor proteins involved in the translation of transcribed mRNA at the ribosome. The inhibition of these initiation factors prevents the initiation and translation of many proteins whose functions are essential to the rapid growth and proliferation of cancer cells.
Eukaryotic translation initiation factor 4E, also known as eIF4E, is a protein that in humans is encoded by the EIF4E gene.
Eukaryotic translation initiation factor 4 gamma 2 is a protein that in humans is encoded by the EIF4G2 gene.
Eukaryotic translation initiation factor 4 gamma 1 is a protein that in humans is encoded by the EIF4G1 gene.
Ribosomal protein S6 kinase beta-1 (S6K1), also known as p70S6 kinase, is an enzyme that in humans is encoded by the RPS6KB1 gene. It is a serine/threonine kinase that acts downstream of PIP3 and phosphoinositide-dependent kinase-1 in the PI3 kinase pathway. As the name suggests, its target substrate is the S6 ribosomal protein. Phosphorylation of S6 induces protein synthesis at the ribosome.
MAP kinase-interacting serine/threonine-protein kinase 1 is an enzyme that in humans is encoded by the MKNK1 gene.
Ribosomal protein S6 kinase beta-2 is an enzyme that in humans is encoded by the RPS6KB2 gene.
Eukaryotic translation initiation factor 4 gamma 3 is a protein that in humans is encoded by the EIF4G3 gene. The gene encodes a protein that functions in translation by aiding the assembly of the ribosome onto the messenger RNA template. Confusingly, this protein is usually referred to as eIF4GII, as although EIF4G3 is the third gene that is similar to eukaryotic translation initiation factor 4 gamma, the second isoform EIF4G2 is not an active translation initiation factor.
Eukaryotic translation initiation factor 4B is a protein that in humans is encoded by the EIF4B gene.
Regulatory-associated protein of mTOR also known as raptor or KIAA1303 is an adapter protein that is encoded in humans by the RPTOR gene. Two mRNAs from the gene have been identified that encode proteins of 1335 and 1177 amino acids long.
Eukaryotic translation initiation factor 4E type 2 is a protein that in humans is encoded by the EIF4E2 gene. It belongs to the eukaryotic translation initiation factor 4E family.
Eukaryotic translation initiation factor 4E-binding protein 2 is a protein that in humans is encoded by the EIF4EBP2 gene.
Eukaryotic translation initiation factor 4E-binding protein 3 is a protein that in humans is encoded by the EIF4EBP3 gene.
The Akt signaling pathway or PI3K-Akt signaling pathway is a signal transduction pathway that promotes survival and growth in response to extracellular signals. Key proteins involved are PI3K and Akt.
GCN2 is a serine/threonine-protein kinase that senses amino acid deficiency through binding to uncharged transfer RNA (tRNA). It plays a key role in modulating amino acid metabolism as a response to nutrient deprivation.
mTOR inhibitors are a class of drugs that inhibit the mammalian target of rapamycin (mTOR), which is a serine/threonine-specific protein kinase that belongs to the family of phosphatidylinositol-3 kinase (PI3K) related kinases (PIKKs). mTOR regulates cellular metabolism, growth, and proliferation by forming and signaling through two protein complexes, mTORC1 and mTORC2. The most established mTOR inhibitors are so-called rapalogs, which have shown tumor responses in clinical trials against various tumor types.
mTORC1, also known as mammalian target of rapamycin complex 1 or mechanistic target of rapamycin complex 1, is a protein complex that functions as a nutrient/energy/redox sensor and controls protein synthesis.
Eukaryotic initiation factor 4F (eIF4F) is a heterotrimeric protein complex that binds the 5' cap of messenger RNAs (mRNAs) to promote eukaryotic translation initiation. The eIF4F complex is composed of three non-identical subunits: the DEAD-box RNA helicase eIF4A, the cap-binding protein eIF4E, and the large "scaffold" protein eIF4G. The mammalian eIF4F complex was first described in 1983, and has been a major area of study into the molecular mechanisms of cap-dependent translation initiation ever since.
Anne-Claude Gingras is a senior investigator at Lunenfeld-Tanenbaum Research Institute, and a professor in the department of molecular genetics at the University of Toronto. She is an expert in mass spectrometry based proteomics technology that allows identification and quantification of protein from various biological samples.
