All tags Cancer p38 MAPK signaling and phosphorylation

p38 MAPK signaling and phosphorylation

by Seán Mac Fhearraigh PhD

p38 MAPK signaling regulates numerous pathways that control cell death, G1 arrest, inflammation as well as ROS regulation.

The p38 MAPK family contains four genes which include MAPK14 which encodes p38α, MAPK11 which encodes p38β, MAPK12 which encodes p38γ and MAPK13 which encodes p38δ [Wagner and Nebreda, 2009]. The first member of the p38 MAPK family was originally independently identified by four groups and was found to be a homologue of the S. cerevisiae protein, Hog1 [Cuadrado and Nebreda, 2010].

View our p38 MAPK interactive pathway

p38 is activated following phosphorylation within the activation loop sequence Thr-Gly-Tyr. The dual-specificity MAPKKs phosphorylate p38 MAPKs following a range of stimuli. MAPKK6 can phosphorylate all four p38 MAPK family members, whereas MAPKK3 can phosphorylate p38α / γ / δ, with MAPKK4 only phosphorylating p38α [Cuadrado and Nebreda, 2010].

Activated p38 phosphorylates transcription factors such as p53, activating transcription factor 2 (ATF-2), myocyte specific enhancer 2 (MEF2) and also protein kinases including mitogen and stress activated protein kinase 1 (MSK1)MAP kinase-interacting Ser/Thr kinase 1 and 2 (MNK1/2) and MAPK activated kinase 2 (MAPKK/MK2) [Wagner and Nebreda, 2009]. 

The p38 MAPK promotes G1 arrest through the phosphorylation of cyclin D, resulting in its degradation and the induction of Cdk2/cyclin E inhibitor p21[Densham et al. 2008; Todd et al., 2004]. Furthermore, Taxol treatment has been shown to activate JNK and p38 MAPK, resulting in downregulation of the reactive oxygen species (ROS) inhibitor, UCP2 (mitochondrial uncoupling protein 2) and activation of the AP-1 transcription factor complex proteins, ATF-2 and ELK1 [Selimovic et al., 2008].

Treatment of cells with the chemotherapeutic agent, sodium arsenite, results in the p38-dependent activation of the forkhead transcription factor, FOXO3a, resulting in the upregulation of BimEL [Cai and Xia, 2008]. Furthermore, p38 MAPK has also been shown to phosphorylate BimEL in response to arsenite treatment resulting in cell death [Cai et al., 2006].

References

  • Cuadrado, A. and A. R. Nebreda (2010). "Mechanisms and functions of p38 MAPK signalling." Biochem J 429(3): 403-17.
  • Wagner, E. F. and A. R. Nebreda (2009). "Signal integration by JNK and p38 MAPK pathways in cancer development." Nat Rev Cancer 9(8): 537-49.
  • Densham, R. M., D. E. Todd, et al. (2008). "ERK1/2 and p38 cooperate to delay progression through G1 by promoting cyclin D1 protein turnover." Cell Signal 20(11): 1986-94.
  • Todd, D. E., R. M. Densham, et al. (2004). "ERK1/2 and p38 cooperate to induce a p21CIP1-dependent G1 cell cycle arrest." Oncogene 23(19): 3284-95.
  • Selimovic,D., M.Hassan, et al. (2008). "Taxol induced mitochondrial stress in melanoma cells is mediated by activation of c Jun N terminal kinase (JNK) and p38 pathways via uncoupling protein 2." Cell Signal 20(2): 311-22.
  • Cai, B., S. H. Chang, et al. (2006). "p38 MAP kinase mediates apoptosis through phosphorylation of BimEL at Ser-65." J Biol Chem 281(35): 25215-22.
  • Cai, B. and Z. Xia (2008). "p38 MAP kinase mediates arsenite-induced apoptosis through FOXO3a activation and induction of Bim transcription." Apoptosis 13(6): 803-10.
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