Disease relevance of Eif4ebp1

• Insulin fails to stimulate muscle protein synthesis in sepsis despite unimpaired signaling to 4E-BP1 and S6K1 [1].
• Inactivation of eIF2B and phosphorylation of PHAS-I in heat-shocked rat hepatoma cells [2].
• Physiological hyperinsulinemia increased p70(S6K) (P < 0.05) but not PHAS-I phosphorylation (P = 0.98) [3].
• Incubation of hepatocytes under hypoxia increases binding of translation initiation factor eIF-4E to its inhibitory regulator 4E-BP1, and this correlates with dephosphorylation of 4E-BP1 [4].
• Phosphorylation of eIF2alpha and eIF4E and the association of eIF4E with 4E-BP1 were also greater than control values after ischemia but only in hearts perfused with glucose plus palmitate [5].

High impact information on Eif4ebp1

• Nonphosphorylated PHAS-I bound to initiation factor 4E (eIF-4E) and inhibited protein synthesis [6].
• PHAS-I as a link between mitogen-activated protein kinase and translation initiation [6].
• Serine-64 in PHAS-I was rapidly phosphorylated by mitogen-activated (MAP) kinase, the major insulin-stimulated PHAS-I kinase in adipocyte extracts [6].
• Regulation of protein synthesis by cholecystokinin in rat pancreatic acini involves PHAS-I and the p70 S6 kinase pathway [7].
• Increasing cAMP with forskolin decreased PHAS-I phosphorylation and markedly increased the amount of eIF-4E bound to PHAS-I, effects consistent with an action of cAMP to inhibit protein synthesis [8].

Biological context of Eif4ebp1

• Addition of AII to quiescent aortic SMC potently increased the phosphorylation of 4E-BP1 as revealed by a decreased electrophoretic mobility and an increased phosphate content of the protein [9].
• Ischaemia induces changes in the association of the binding protein 4E-BP1 and eukaryotic initiation factor (eIF) 4G to eIF4E in differentiated PC12 cells [10].
• PC12 cells were used to study the signal transduction pathway leading to phosphorylation of PHAS-I [11].
• However, in view of its tissue distribution and the fact that the protein is phosphorylated in response to insulin, we speculate that PHAS-I is important in insulin action [12].
• The nucleotide and deduced amino acid sequences of PHAS-I differ from any that have been reported, and homology screening provided no clues concerning the function of the protein [12].

Anatomical context of Eif4ebp1

• To investigate the molecular basis of the hypertrophic action of angiotensin II (AII) in vascular smooth muscle cells (SMC), we have examined the ability of the hormone to regulate the function of the translational repressor 4E-binding protein 1 (4E-BP1) [9].
• PGF2alpha also induced eIF4E and 4E-BP1 phosphorylation, global protein synthesis, and basic fibroblast growth factor-2 (bFGF-2) expression in VSMC [13].
• Endotoxin disrupts the leucine-signaling pathway involving phosphorylation of mTOR, 4E-BP1, and S6K1 in skeletal muscle [14].
• We examined whether LPS alters 4E-BP1 phosphorylation in macrophages [15].
• Arginine and Leucine regulate p70 S6 kinase and 4E-BP1 in intestinal epithelial cells [16].

Associations of Eif4ebp1 with chemical compounds

• PGF2alpha-induced phosphorylation of eIF4E and 4E-BP1 was also found to be sensitive to inhibition by both wortmannin and rapamycin [13].
• Further characterization of 4E-BP1 phosphorylation by phosphoamino acid analysis and phosphopeptide mapping revealed that 4E-BP1 is phosphorylated on eight distinct peptides containing serine and threonine residues in AII-treated cells [9].
• The treatment with N-acetyl-cysteine (NAC) completely abolishes the H2O2-induced decrease in eIF4E phosphorylated levels, whereas the decrease in 4E-BP1 phosphorylated levels and eIF4F activity inhibition are significantly but not fully reversed [17].
• We examined phosphadityl inositol (PI) 3-kinase in angiotensin II-induced 4E-BP1 phosphorylation in cultured rat vascular smooth muscle cells [18].
• In conclusion, l-Arginine regulates p70 S6 kinase activity and phosphorylation of 4E-BP1 through mTOR signaling pathway, which involves system y(+), cationic amino acid transporters [16].

Physical interactions of Eif4ebp1

• In cultured cells, growth factor-induced phosphorylation of two translation modulators, p70 S6 kinase and eukaryotic initiation factor 4E-binding protein 1 (4E-BP1), is blocked by nanomolar concentrations of the immunosuppressant rapamycin [19].
• Dissociation of the eukaryotic initiation factor-4E/4E-BP1 complex involves phosphorylation of 4E-BP1 by an mTOR-associated kinase [20].
• This results in phosphorylation of the ribosomal protein S6 kinase 1 (S6K1) and eukaryotic initiation factor 4E-binding protein-1 (4E-BP1), two proteins involved in the initiation phase of protein synthesis [21].

Enzymatic interactions of Eif4ebp1

• The mammalian target of rapamycin (mTOR) has been proposed to directly phosphorylate 4E-BP1 [19].
• Leptin increased mammalian target of rapamycin (mTor) that phosphorylates 4E-BP1 [22].

Regulatory relationships of Eif4ebp1

• Results from affinity chromatography on m7GTP-agarose demonstrated that AII-induced phosphorylation of 4E-BP1 promotes its dissociation from eIF4E in target cells [9].
• This excludes a role for MAPK in NGF- and EGF-induced PHAS-I phosphorylation in PC12 cells [11].
• Inhibition of both the p42/p44 MAPK pathway (PD 98059) and the p38 MAPK pathway (SB 203580) failed to alter LPS-induced 4E-BP1 phosphorylation [15].
• IGF-I induced phosphorylation of S6K1 and 4E-BP1 in heart is impaired by acute alcohol intoxication [23].
• In agreement, BDNF induced the phosphorylation of mammalian TOR (target of rapamycin) and enhanced its kinase activity toward eIF4E-binding protein-1 [24].

Other interactions of Eif4ebp1

• Results obtained with antibodies, immobilized PHAS-I, and a messenger RNA cap affinity resin indicated that PHAS-I did not bind eIF-4E when serine-64 was phosphorylated [6].
• 40 S ribosomal protein S6, a target of p70(S6K), and 4E-BP1, a target of mTOR, were both phosphorylated within 15-25 min of T3 treatment and could be inhibited by wortmannin and rapamycin [25].
• Overall, the results suggest that the leucine-induced enhancement of protein synthesis and the phosphorylation states of 4E-BP1 and S6K1 are facilitated by the transient increase in serum insulin [26].
• In contrast, glucagon repressed both basal and amino acid-induced signaling through mTOR, as assessed by changes in the phosphorylation of 4E-BP1 and S6K1 [27].
• Activation of Akt stimulated signaling through the protein kinase mammalian target of rapamycin, as evidenced by increased phosphorylation of two of its effectors, the ribosomal protein S6 kinase and the eukaryotic initiation factor eIF4E binding protein 1 [28].

Analytical, diagnostic and therapeutic context of Eif4ebp1

• Western blots (WB) were developed with 4E-BP1 antibody [15].
• Molecular cloning and tissue distribution of PHAS-I, an intracellular target for insulin and growth factors [12].
• When translated in vitro and subjected to SDS/PAGE, PHAS-I migrates anomalously, having an apparent M(r) of 21,000 [12].
• Oral administration of leucine stimulates protein synthesis in association with hyperphosphorylation of the translational repressor, eukaryotic initiation factor (eIF) 4E binding protein 1 (4E-BP1), resulting in enhanced availability of the mRNA cap-binding protein eIF4E, for binding eIF4G and forming the active eIF4F complex [29].
• Rapamycin blocked the activation of p70 S6 kinase in response to partial hepatectomy in a dose-dependent manner, but 4E-BP1 phosphorylation was not inhibited [19].

References