MITOGEN-ACTIVATED PROTEIN-KINASES ACTIVATE THE SERINE THREONINE KINASES MNK1 AND MNK2/

Mitogen-activated protein (MAP) kinases bind tightly to many of their physiologically relevant substrates. We have identified a new subfamil y of murine serine/threonine kinases, whose members, MAP kinase-intera cting kinase 1 (Mnk1) and Mnk2, bind tightly to the growth factor-regu lated MAP kinases, Erk1 and Erk2. Mnk1, but not Mnk2, also binds stron gly to the stress-activated kinase, p38. Mnk1 complexes more strongly with inactive than active Erk, implying that Mnk and Erk may dissociat e after mitogen stimulation. Erk and p38 phosphorylate Mnk1 and Mnk2, which stimulates their in vitro kinase activity toward a substrate, eu karyotic initiation factor-4E (eIF-4E). Initiation factor eIF-4E is a regulatory phosphoprotein whose phosphorylation is increased by insuli n in an Erk-dependent manner. Irt vitro, Mnk1 rapidly phosphorylates e IF-4E at the physiologically relevant site, Ser209. In cells, Mnk1 is post-translationally modified and enzymatically activated in response to treatment with either peptide growth factors, phorbol esters, aniso mycin or UV, Mitogen- and stress-mediated Mnk1 activation is blocked b y inhibitors of MAP kinase kinase 1 (Mkk1) and p38, demonstrating that Mnk1 is downstream of multiple MAP kinases, Mnk1 may define a converg ence point between the growth factor-activated and one of the stress-a ctivated protein kinase cascades and is a candidate to phosphorylate e IF-4E in cells.