The Regulation of eIF4E Controls the Rate of Initiation

The 4F complex is particularly important in controlling the rate of protein translation. As described above, 4F is a complex consisting of 4E, which binds to the m7G cap structure at the 5' end of the mRNA, and 4G, which serves as a scaffolding protein. In addition to binding 4E, 4G binds to eIF-3, which links the complex to the 40S ribosomal subunit. It also binds 4A and 4B, the ATPase-helicase complex that helps unwind the RNA (Figure 38-7).

4E is responsible for recognition of the mRNA cap structure, which is a rate-limiting step in translation. This process is regulated at two levels. Insulin and mi-togenic growth factors result in the phosphorylation of 4E on ser 209 (or thr 210). Phosphorylated 4E binds to the cap much more avidly than does the nonphospho-rylated form, thus enhancing the rate of initiation. A component of the MAP kinase pathway (see Figure 43-8) appears to be involved in this phosphorylation reaction.

The activity of 4E is regulated in a second way, and this also involves phosphorylation. A recently discovered set of proteins bind to and inactivate 4E. These proteins include 4E-BP1 (BP1, also known as PHAS-1) and the closely related proteins 4E-BP2 and 4E-BP3. BP1 binds with high affinity to 4E. The [4E]*[BP1] association prevents 4E from binding to 4G (to form 4F). Since this interaction is essential for the binding of 4F to the ribosomal 40S subunit and for correctly positioning this on the capped mRNA, BP-1 effectively inhibits translation initiation.

Insulin and other growth factors result in the phos-phorylation of BP-1 at five unique sites. Phosphorylation of BP-1 results in its dissociation from 4E, and it cannot rebind until critical sites are dephosphorylated. The protein kinase responsible has not been identified, but it appears to be different from the one that phos-phorylates 4E. A kinase in the mammalian target of rapamycin (mTOR) pathway, perhaps mTOR itself, is involved. These effects on the activation of 4E explain in part how insulin causes a marked posttranscriptional

Figure 38-7. Activation of eIF-4E by insulin and formation of the cap binding eIF-4F complex. The 4F-cap mRNA complex is depicted as in Figure 38-6. The 4F complex consists of eIF-4E (4E), eIF-4A, and eIF-4G. 4E is inactive when bound by one of a family of binding proteins (4E-BPs). Insulin and mitogenic factors (eg, IGF-1, PDGF, interleukin-2, and angiotensin II) activate a serine protein kinase in the mTOR pathway, and this results in the phosphorylation of 4E-BP. Phosphorylated 4E-BP dissociates from 4E, and the latter is then able to form the 4F complex and bind to the mRNA cap. These growth peptides also phosphorylate 4E itself by activating a component of the MAP kinase pathway. Phosphorylated 4E binds much more avidly to the cap than does nonphosphorylated 4E.

Figure 38-7. Activation of eIF-4E by insulin and formation of the cap binding eIF-4F complex. The 4F-cap mRNA complex is depicted as in Figure 38-6. The 4F complex consists of eIF-4E (4E), eIF-4A, and eIF-4G. 4E is inactive when bound by one of a family of binding proteins (4E-BPs). Insulin and mitogenic factors (eg, IGF-1, PDGF, interleukin-2, and angiotensin II) activate a serine protein kinase in the mTOR pathway, and this results in the phosphorylation of 4E-BP. Phosphorylated 4E-BP dissociates from 4E, and the latter is then able to form the 4F complex and bind to the mRNA cap. These growth peptides also phosphorylate 4E itself by activating a component of the MAP kinase pathway. Phosphorylated 4E binds much more avidly to the cap than does nonphosphorylated 4E.

increase of protein synthesis in liver, adipose tissue, and muscle.

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