Identification of regulatory phosphorylation sites in mitogen-activated protein kinase (MAPK)-activated protein kinase-1a/p90(rsk) that are inducible by MAPK

Kevin N. Dalby, Nick Morrice, F. Barry Caudwell, Joseph Avruch, Philip Cohen

    Research output: Contribution to journalArticlepeer-review

    301 Citations (Scopus)

    Abstract

    Mitogen-activated protein kinase-activated protein kinase-1 (MAPKAP-K1; also known as p90(rsk)) contains two protein kinase domains in a single polypeptide. The N-terminal kinase domain is necessary for the phosphorylation of peptide substrates, whereas the C-terminal kinase domain is required for full activation of the N-terminal domain. Here we identify six sites in MAPKAP-K1a that become phosphorylated in transfected COS-1 cells. The inactive form of MAPKAP-K1a in unstimulated cells is partially phosphorylated at Ser222 and Ser733. Stimulation with phorbol 12- myristate 13-acetate induces the phosphorylation of Thr360, Ser364, Thr574, and Ser381 and increases the phosphorylation of Ser222 and Ser733. Our data indicate that mitogen-activated protein kinase activates the C-terminal kinase domain by phosphorylating thr574 and contributes to the activation of the N-terminal kinase domain by phosphorylating Ser364. The activated C-terminal domain phosphorylates Ser381, which, together with phosphorylation of Ser364, activates the N-terminal kinase domain. The phosphorylation of Ser222 and Ser733, which can be catalyzed by the N-terminal domain, does not activate MAPKAP-K1a per se, but Ser222 phosphorylation appears to be required for activation. Ser222, Ser364, and Ser381 are situated in analogous positions to phosphorylation sites in protein kinase B, protein kinase C, and p70(S6K), suggesting a common mechanism of activation for these growth factor-stimulated protein kinases.

    Original languageEnglish
    Pages (from-to)1496-1505
    Number of pages10
    JournalJournal of Biological Chemistry
    Volume273
    Issue number3
    DOIs
    Publication statusPublished - 16 Jan 1998

    Fingerprint Dive into the research topics of 'Identification of regulatory phosphorylation sites in mitogen-activated protein kinase (MAPK)-activated protein kinase-1a/p90(rsk) that are inducible by MAPK'. Together they form a unique fingerprint.

    Cite this