Differential activation of p38MAPK isoforms by MKK6 and MKK3

Gaëlle Remy, Ana M. Risco, Francisco A. Iñesta-Vaquera, Bárbara González-Terán, Guadalupe Sabio, Roger J. Davis, Ana Cuenda (Lead / Corresponding author)

    Research output: Contribution to journalArticlepeer-review

    121 Citations (Scopus)

    Abstract

    All four members of the mammalian p38 mitogen-activated protein kinase (MAPK) family (p38α, p38β, p38γ and p38δ) are activated by dual phosphorylation in the TGY motif in the activation loop. This phosphorylation is mediated by three kinases, MKK3, MKK6 and MKK4, at least in vitro. The role of these MKK in the activation of p38α has been demonstrated in studies using fibroblasts that lack MKK3 and/or MKK6. Nonetheless, the physiological upstream activators of the other p38MAPK isoforms have not yet been reported using MKK knockout cells. In this study, we examined p38β, γ and δ activation by MKK3 and MKK6, in cells lacking MKK3, MKK6 or both. We show that MKK3 and MKK6 are both essential for the activation of p38γ and p38β induced by environmental stress, whereas MKK6 is the major p38γ activator in response to TNFα. In contrast, p38δ activation by ultraviolet radiation, hyperosmotic shock, anisomycin or by TNFα is mediated by MKK3. Moreover, in response to osmotic stress, MKK3 and MKK6 are crucial in regulating the phosphorylation of the p38γ substrate hDlg and its activity as scaffold protein. These data indicate that activation of distinct p38MAPK isoforms is regulated by the selective and synchronized action of two kinases, MKK3 and MKK6, in response to cell stress.

    Original languageEnglish
    Pages (from-to)660-667
    Number of pages8
    JournalCellular Signalling
    Volume22
    Issue number4
    Early online date11 Dec 2009
    DOIs
    Publication statusPublished - 1 Apr 2010

    Keywords

    • MAP kinase
    • MKK3
    • MKK6
    • p38β
    • p38γ
    • p38δ

    ASJC Scopus subject areas

    • Cell Biology

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