MAP kinase-interacting kinase 1 (Mnk1) and Mnk2, members of the Ser/Thr protein kinase family, bind tightly to the growth factor-regulated MAP kinases, Erk1 and Erk2. Erk and p38 phosphorylate MNK1 and Mnk2, which stimulates their in vitro kinase activity toward a substrate, eukaryotic initiation factor-4E (eIF-4E). Overexpression of Mnk2 results in increased phosphorylation of endogenous eIF-4E, showing that it can act as an eIF-4E kinase in vivo. Mnk2 may play a role in the response to environmental stress and cytokines. This ubiquitiously expressed protein appears to regulate transcription by phosphorylating eIF-4E, thus increasing the affinity of this protein for the 7-methylguanosine-containing mRNA cap. Expression of active mutants of MNK1 and MNK2 in 293 cells diminishes cap-dependent translation relative to cap-independent translation in a transient reporter assay. Human Mnk2 is homologous to murine Mnk2 (approximately 94% identical) and human Mnk1 (71% identical). In vitro phosphorylation studies show that Mnk2 is a significantly better substrate than Mnk1 for extracellular signal-regulated kinase 2 (Erk2), p38MAPKalpha, and p38MAPKbeta. Mnk2 has also been shown to interact with the C-terminal regions of eIF-4G1 and eIF-4G2.