The N and C Termini of the Splice Variants of the Human Mitogen-Activated Protein Kinase-Interacting Kinase Mnk2 Determine Activity and Localization

Abstract

The cap-binding eukaryotic initiation factor eIF4E is phosphorylated by the mitogen-activated protein (MAP) kinase-interacting kinases (Mnk's). Three forms of the Mnk's exist in human cells: Mnk1, Mnk2a, and Mnk2b. These last two are derived from the same gene by alternative splicing and differ only at their C termini. While Mnk2a contains a MAP kinase-binding site in this region, Mnk2b lacks such a sequence and is much less readily activated by MAP kinases in vitro. Expression of Mnk2b in mammalian cells leads to increased phosphorylation of eIF4E, showing that it acts as an eIF4E kinase in vivo. While Mnk2a is cytoplasmic, a substantial amount of Mnk2b is found in the nucleus. Both enzymes contain a stretch of basic residues in their N termini that plays a role in binding to eIF4G and functions as a nuclear localization signal. Binding of eIF4G or nuclear import appears to be regulated by the C terminus of Mnk2a. Furthermore, the MAP kinase-binding site of Mnk2a regulates nuclear entry. Within the nucleus, Mnk2b and certain variants of Mnk2a that are present in the nucleus colocalize with the promyelocytic leukemia protein PML, which also binds to eIF4E.

The gene encoding the splicing factor SF2/ASF is a proto-oncogene

“…30). The MNK2 gene, MKNK2, is alternatively spliced, generating two catalytically active isoforms that are differentially regulated and localized 31 . Overexpression of SF2/ASF resulted in increased expression of the MNK2b isoform and a corresponding reduction in the MNK2a isoform ( Fig.…”

“…4d) prompted us to investigate whether the induction of isoform MNK2b changes the phosphorylation state of eIF4E 33 . The MAPKs ERK1, ERK2 and p38 are phosphorylated by upstream MAPK kinases, and they in turn phosphorylate MNK1 and MNK2, which is usually required for full activity of MNK1 and MNK2 kinases 31 . Remarkably, although SF2/ASF did not enhance phosphorylation of ERK1/2 or p38, it strongly enhanced phosphorylation of eIF4E on Ser209 (Fig.…”

ERK and p38 MAPK-Activated Protein Kinases: a Family of Protein Kinases with Diverse Biological Functions

“…MNK2B lacks the C-terminal 52 amino acid containing the D domain (Fig. 4) and has been shown to be a poor substrate for ERK1/2 and p38 in vitro (170). The D domain of MNK1 consists of Leu-Ala-Arg-ArgArg (Fig.…”

Mnk kinases in cytokine signaling and regulation of cytokine responses

“…As in the case of Mnk1, Mnk2 is also known to alternatively spliced into two isoforms Mnk2a and Mnk2b. The two isoforms differ in their carboxyl terminal ends due to an alternative exon 13 [5]. Mnk2b is shorter than Mnk2a, lacks a MAPK binding domain, exhibits low kinase activity towards eIF4E and is also localized in the nucleus [5].…”

“…The two isoforms differ in their carboxyl terminal ends due to an alternative exon 13 [5]. Mnk2b is shorter than Mnk2a, lacks a MAPK binding domain, exhibits low kinase activity towards eIF4E and is also localized in the nucleus [5]. Mnk2b is known to interact with the estrogen receptor (ER) β leading to the suggestion that Mnk2b mediated phosphorylation of ERβ may result in the transcriptional regulation of ER regulated genes [135].…”