Disease relevance of EIF4EBP1

• We found that PTX induced the hyperphosphorylation of 4E-BP1 in the breast cancer cell line, MDA MB 231, which reduced its association with eIF-4E, but did not alter the expression and phosphorylation of eIF-4E [1].
• Vesicular stomatitis virus infection alters the eIF4F translation initiation complex and causes dephosphorylation of the eIF4E binding protein 4E-BP1 [2].
• We report here that hypoxia inhibits mRNA translation by suppressing multiple key regulators, including eIF2alpha, eEF2, and the mammalian target of rapamycin (mTOR) effectors 4EBP1, p70S6K, and rpS6, independent of HIF [3].
• Activation of the translational suppressor 4E-BP1 following infection with encephalomyocarditis virus and poliovirus [4].
• Here we show that early in adenovirus infection, 4E-BP1 and its related protein 4E-BP2 are phosphorylated and hence inactivated [5].
• 4E-BP1 was hyperphosphorylated in 4 of 7 melanoma cell lines harboring both BRAF and PTEN mutations compared with untransformed melanocytes or RAS/RAF/PTEN wild-type melanoma cells [6].

Psychiatry related information on EIF4EBP1

• Levels of mTOR and its downstream targets 4E-BP1, eEF2, and eEF2 kinase in relationships with tau in Alzheimer's disease brain [7].

High impact information on EIF4EBP1

• While 4EGI-1 displaces eIF4G from eIF4E, it effectively enhances 4E-BP1 association both in vitro and in cells [8].
• mTOR controls cell growth, in part by regulating p70 S6 kinase alpha (p70alpha) and eukaryotic initiation factor 4E binding protein 1 (4EBP1) [9].
• Thus, raptor is an essential scaffold for the mTOR-catalyzed phosphorylation of 4EBP1 and mediates TOR action in vivo [9].
• Raptor is a 150 kDa mTOR binding protein that also binds 4EBP1 and p70alpha [9].
• Partial inhibition of raptor expression by RNA interference (RNAi) reduces mTOR-catalyzed 4EBP1 phosphorylation in vitro [9].

Chemical compound and disease context of EIF4EBP1

• Hypoxia Inhibits Protein Synthesis through a 4E-BP1 and Elongation Factor 2 Kinase Pathway Controlled by mTOR and Uncoupled in Breast Cancer Cells [10].

Biological context of EIF4EBP1

• Regulation of 4E-BP1 phosphorylation: a novel two-step mechanism [11].
• Further investigation by altering FRAP's nuclear shuttling activity with exogenous nuclear import and export signals has yielded results that are consistent with a direct link between nuclear shuttling of FRAP and mitogenic stimulation of p70(s6k) activation and 4E-BP1 phosphorylation [12].
• Our results suggest that 4E-BP1-mediated control of apoptosis occurs through qualitative rather than quantitative changes in protein synthesis, mediated by a dynamic interplay between cap-dependent and cap-independent processes [13].
• 4E-BP1 plays key roles in cell proliferation, growth, and survival [14].
• BACKGROUND: The mammalian target of rapamycin, mTOR, is a serine/threonine kinase that controls cell growth and proliferation via the translation regulators eukaryotic initiation factor 4E (eIF4E) binding protein 1 (4E-BP1) and ribosomal protein S6 kinase 1 (S6K1) [15].

Anatomical context of EIF4EBP1

• These findings show: that phosphorylation events govern the proapoptotic potency of 4E-BP1, that 4E-BP1 is proapoptotic in normal as well as transformed fibroblasts, and that malignant transformation is associated with a higher requirement for cap-dependent translation to inhibit apoptosis [13].
• Recruitment of mRNAs to the ribosome is enhanced by phosphorylation of eIF4E, the cap-binding protein, and PHAS-I, a protein that specifically binds eIF4E [16].
• Insulin and/or amino acids increased, and rapamycin decreased, the reactivity of all three antibodies with PHAS-I in both HEK293 cells and 3T3-L1 adipocytes [17].
• In a first part, we show that the expression of 4E-BP1 protein and transcript decreases in hematopoietic cell lines cultivated in the presence of phorbol 12-myristate 13-acetate (PMA) [18].
• Resistance exercise increases AMPK activity and reduces 4E-BP1 phosphorylation and protein synthesis in human skeletal muscle [19].

Associations of EIF4EBP1 with chemical compounds

• The mechanism involves the ability of this integrin to stimulate the phosphorylation and inactivation of 4E-binding protein (4E-BP1), a translational repressor that inhibits the function of eukaryotic translation initiation factor 4E (eIF-4E) [20].
• Tel1p phosphorylates serine in an SQ motif in PHAS-I [21].
• Inhibition of FRAP nuclear export by LMB coincides with diminished p70(s6k) activation and 4E-BP1 phosphorylation [12].
• TOS motif-mediated raptor binding regulates 4E-BP1 multisite phosphorylation and function [15].
• Cotreatment with a histone deacetylase inhibitor (an indirect inhibitor of cdk activity), purvalanol A and roscovitine (direct cdk inhibitors), and the reduction of cyclin B expression using RNA interference decreased the hyperphosphorylation of 4E-BP1 in PTX treated cells [1].

Physical interactions of EIF4EBP1

• Herein we demonstrate that raptor binds to p70S6k and 4E-BP1 through their respective TOS (conserved TOR signaling) motifs to be required for amino acid- and mTOR-dependent regulation of these mTOR substrates in vivo [22].
• In this study we examine whether paclitaxel (PTX) alters the expression and/or phosphorylation of the translation initiation proteins, eukaryotic initiation factor 4E (eIF-4E) and 4E-binding protein (4E-BP1), a suppressor of eIF-4E in the dephosphorylated state [1].
• Recently, amino acid sufficiency has been demonstrated to selectively regulate p70 S6 kinase (p70(s6k)) and eukaryotic initiation factor 4E-binding protein 1 (4E-BP1), both of which are targeted by the anti-proliferative drug rapamycin [23].
• Since mTOR activates both the 40S ribosomal protein S6 kinase ((p)70(s6k)) and the eukaryotic initiation factor 4E-binding protein-1 (4E-BP1), RAP blocks activation of these downstream signaling elements, which results in cell cycle arrest in the G1 arrest [24].
• IGF-1 treatment increased the phosphorylation of eukaryotic initiation factor (eIF)-4E-binding protein 1 (4E-BP1), exclusively at Thr-36 and Thr-45 residues, and eIF-4G phosphorylation at Ser-1108 [25].

Enzymatic interactions of EIF4EBP1

• FRAP/mTOR has been reported to phosphorylate 4E-BP1 directly in vitro [11].
• The homology is most striking in the middle region of the protein, which contains the eIF4E binding motif and residues that are phosphorylated in 4E-BP1 [26].
• The activated mTOR kinase phosphorylates/ activates ribosomal protein S6 kinase (p70S6K) and phosphorylates/inactivates eukaryotic initiation factor 4E-binding protein-1 (4E-BP1), resulting in the initiation of translation and cell-cycle progression [27].

Regulatory relationships of EIF4EBP1

• Ser-64 and Ser-111 in PHAS-I are dispensable for insulin-stimulated dissociation from eIF4E [28].
• Pharmacological and genetic evidence indicates that the mTOR/p70S6K pathway is involved in the control of PHAS-I and -II [29].
• We present evidence that FRAP controls 4E-BP1 and p70(s6k) phosphorylation indirectly by restraining a phosphatase [30].
• PRL also stimulated phosphorylation of 4E-BP1 in Nb2 cells [27].
• The extracellular signal-regulated kinase pathway regulates the phosphorylation of 4E-BP1 at multiple sites [31].

Other interactions of EIF4EBP1

• Taken together, our results suggest that 4E-BP1 phosphorylation by FRAP/mTOR on Thr-37 and Thr-46 is a priming event for subsequent phosphorylation of the carboxy-terminal serum-sensitive sites [11].
• Furthermore, we demonstrate that 4E-BP1 competes with p220 for binding to eIF-4E [32].
• The function of RAFT1 in the rapamycin-sensitive pathway and its connection to downstream components of the pathway, such as p70 S6 kinase and 4E-BP1, are poorly understood [33].
• Stimulation of protein synthesis, eukaryotic translation initiation factor 4E phosphorylation, and PHAS-I phosphorylation by insulin requires insulin receptor substrate 1 and phosphatidylinositol 3-kinase [16].
• A point mutation of the TOS motif also eliminates all in vitro mTOR-catalyzed 4E-BP1 phosphorylation and abolishes the raptor-dependent component of mTOR-catalyzed p70S6k phosphorylation in vitro [22].
• The use of a pharmacological inhibitor and dominant-negative or -positive mutants of PI3K all affect 4E-BP1 protein expression and promoter activity in different cell lines [34].

Analytical, diagnostic and therapeutic context of EIF4EBP1

• Western blot analysis indicated a highly significant difference in the phosphorylation status of 4E-BP1 between tumors and resection margins [35].
• We now demonstrate that CCI-779 rapidly inhibits mTOR activity, as indicated by S6 reduction and eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) phosphorylation in two xenograft models of RMS within 24 hours of treatment [36].
• For each individual site, we have analyzed the effects of modification on eIF4E binding using affinity chromatography and surface plasmon resonance analysis, and on the regulatory function of the 4E-BP1 protein using a yeast in vivo model system and a mammalian in vitro translation assay [37].
• PHAS-I was also phosphorylated at a significant rate by casein kinase II and protein kinase C. To investigate sites of phosphorylation, PHAS-I was digested with collagenase and phosphopeptides were resolved by reverse phase high performance liquid chromatography [38].
• Systemic infusion of mixed amino acids significantly stimulated the phosphorylation of 4E-BP1 (P < 0.04) and p70(S6K) (P < 0.001) and the dephosphorylation of eIF2alpha (P < 0.003) in the control group [39].

References