Reactome | Nuclear export of p38 MAPK mediated by its substrate MAPKAPK2 or 3

Nuclear export of p38 MAPK mediated by its substrate MAPKAPK2 or 3

Stable Identifier

R-GGA-442862

Type

Reaction [transition]

Species

Gallus gallus

Compartment

cytosol, nuclear envelope, nucleoplasm

Locations in the PathwayBrowser

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Innate Immune System (Gallus gallus)

- Toll-like receptors (TLR) cascades (Gallus gallus)
  - TLR15 cascade (Gallus gallus)
    - MyD88 cascade initiated on plasma membrane (Gallus gallus)
      - NFkB and MAPK activation mediated by TRAF6 (Gallus gallus)
        
        MAPK activation in TLR cascade (Gallus gallus)
        
        Activated TAK1 mediates p38 MAP kinase phosphorylation (Gallus gallus)
        
        Nuclear export of p38 MAPK mediated by its substrate MAPKAPK2 or 3 (Gallus gallus)
  - TLR2 subfamily cascade (Gallus gallus)
    - MyD88:TIRAP-dependent cascade initiated on plasma membrane (Gallus gallus)
      - NFkB and MAPK activation mediated by TRAF6 (Gallus gallus)
        
        MAPK activation in TLR cascade (Gallus gallus)
        
        Activated TAK1 mediates p38 MAP kinase phosphorylation (Gallus gallus)
        
        Nuclear export of p38 MAPK mediated by its substrate MAPKAPK2 or 3 (Gallus gallus)
  - TLR21 cascade (Gallus gallus)
    - MyD88-dependent cascade initiated on endosome membrane (Gallus gallus)
      - NFkB and MAPK activation mediated by TRAF6 upon TLR7 or TLR21 stimulation (Gallus gallus)
        
        MAPK activation in TLR cascade (Gallus gallus)
        
        Activated TAK1 mediates p38 MAP kinase phosphorylation (Gallus gallus)
        
        Nuclear export of p38 MAPK mediated by its substrate MAPKAPK2 or 3 (Gallus gallus)
  - TLR3 cascade (Gallus gallus)
    - TRAF6 mediated induction of proinflammatory cytokines (Gallus gallus)
      - MAPK activation in TLR cascade (Gallus gallus)
        
        Activated TAK1 mediates p38 MAP kinase phosphorylation (Gallus gallus)
        
        Nuclear export of p38 MAPK mediated by its substrate MAPKAPK2 or 3 (Gallus gallus)
  - TLR4 cascade (Gallus gallus)
    - MyD88:TIRAP-dependent cascade initiated on plasma membrane (Gallus gallus)
      - NFkB and MAPK activation mediated by TRAF6 (Gallus gallus)
        
        MAPK activation in TLR cascade (Gallus gallus)
        
        Activated TAK1 mediates p38 MAP kinase phosphorylation (Gallus gallus)
        
        Nuclear export of p38 MAPK mediated by its substrate MAPKAPK2 or 3 (Gallus gallus)
  - TLR5 cascade (Gallus gallus)
    - MyD88 cascade initiated on plasma membrane (Gallus gallus)
      - NFkB and MAPK activation mediated by TRAF6 (Gallus gallus)
        
        MAPK activation in TLR cascade (Gallus gallus)
        
        Activated TAK1 mediates p38 MAP kinase phosphorylation (Gallus gallus)
        
        Nuclear export of p38 MAPK mediated by its substrate MAPKAPK2 or 3 (Gallus gallus)
  - TLR7 cascade (Gallus gallus)
    - MyD88-dependent cascade initiated on endosome membrane (Gallus gallus)
      - NFkB and MAPK activation mediated by TRAF6 upon TLR7 or TLR21 stimulation (Gallus gallus)
        
        MAPK activation in TLR cascade (Gallus gallus)
        
        Activated TAK1 mediates p38 MAP kinase phosphorylation (Gallus gallus)
        
        Nuclear export of p38 MAPK mediated by its substrate MAPKAPK2 or 3 (Gallus gallus)

General

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Nuclear export of p38 MAPK mediated by its substrate MAPKAPK2 or 3

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The layout of this reaction may differ from that in the pathway view due to the constraints in pathway layout

p38 MAPK alpha does not have a nuclear export signal (NES) and cannot leave the nucleus by itself, but rather needs to be associated with MAP kinase-activated protein kinase 2 (MAPKAPK2 or MK2). The NES of MAPKAPK2 facilitates the transport of both kinases from the nucleus to the cytoplasm but only after MK2 has been phosphorylated by p38alpha.

p38 MAPK alpha phosphorylates MK2 at Thr222, Ser272, and Thr334. The phosphorylation of Thr334 but not the kinase activity of MK2 has been demonstrated to be critical for the nuclear export of the p38 alpha - MK2 complex. Phosphorylation of Thr334 is believed to induce a conformational change in the complex exposing NES prior to interaction with the leptomycin B-sensitive nuclear export receptor.

Literature References

PubMed ID	Title	Journal	Year
9768359	Nuclear export of the stress-activated protein kinase p38 mediated by its substrate MAPKAP kinase-2 Marshall, CJ, Hooper, S, Paterson, HF, Ben-Levy, R, Wilson, R	Curr Biol	1998
12171911	Structure of mitogen-activated protein kinase-activated protein (MAPKAP) kinase 2 suggests a bifunctional switch that couples kinase activation with nuclear export Fulghum, JR, Behrens, AE, Fitzgibbon, MJ, Meng, W, Swenson, LL, Hayakawa, K, Lippke, JA, Ter Haar, E	J Biol Chem	2002