ERK and p38 MAPK-Activated Protein Kinases: a Family of Protein Kinases with Diverse Biological Functions

Department of Cell Biology, Harvard Medical School, 240 Longwood Ave., Boston, MA 02115, USA.
Microbiology and Molecular Biology Reviews (Impact Factor: 14.61). 07/2004; 68(2):320-44. DOI: 10.1128/MMBR.68.2.320-344.2004
Source: PubMed


Conserved signaling pathways that activate the mitogen-activated protein kinases (MAPKs) are involved in relaying extracellular stimulations to intracellular responses. The MAPKs coordinately regulate cell proliferation, differentiation, motility, and survival, which are functions also known to be mediated by members of a growing family of MAPK-activated protein kinases (MKs; formerly known as MAPKAP kinases). The MKs are related serine/threonine kinases that respond to mitogenic and stress stimuli through proline-directed phosphorylation and activation of the kinase domain by extracellular signal-regulated kinases 1 and 2 and p38 MAPKs. There are currently 11 vertebrate MKs in five subfamilies based on primary sequence homology: the ribosomal S6 kinases, the mitogen- and stress-activated kinases, the MAPK-interacting kinases, MAPK-activated protein kinases 2 and 3, and MK5. In the last 5 years, several MK substrates have been identified, which has helped tremendously to identify the biological role of the members of this family. Together with data from the study of MK-knockout mice, the identities of the MK substrates indicate that they play important roles in diverse biological processes, including mRNA translation, cell proliferation and survival, and the nuclear genomic response to mitogens and cellular stresses. In this article, we review the existing data on the MKs and discuss their physiological functions based on recent discoveries.

Download full-text


Available from: John Blenis,
  • Source
    • "Many different stimuli, including growth factors, cytokines and viral infection activate the ERK pathway. P38 mitogenactivated protein kinases are responsive as same as JNK, and involved in cell differentiation, apoptosis and autophagy (Johnson and Lapadat, 2002; Roux and Blenis, 2004; Xia et al., 1995). The phosphorylation levels of p38, ERK and JNK after bacterial stimulation were each highly elevated by 30 min, which indicates that cell signaling was activated in the E. sinensis hemocyte culture system described here. "
    [Show abstract] [Hide abstract]
    ABSTRACT: In order to advance immunological research, a modified primary cell culture method for hemocytes from Eriocheir sinensis (Chinese mitten crab) was established using L-15 medium lacking FBS and CO2 at 28 °C. Under these conditions, cultured cells were stably propagated for 30 days. To evaluate cellular activity, expression levels of certain critical immune-related genes, melanization of the hemocytes, and the phosphorylation status of key molecules in cell signaling pathways were analyzed. mRNA expression level of EsDWD1, EsLecG and EsToll2 was upregulated after LPS, PGN and GLU stimulation. Meanwhile, stimulated by Vibrio parahemolyticus led to the melanization of the hemocytes, and the melanization was more obviously with the increasing concentration of bacteria. Moreover, exposure to V. parahemolyticus significantly induced JNK, ERK and p38 phosphorylation, with the greatest extent of phosphorylation observed 30 min post-induction. Collectively, our results establish a technique for E. sinensis hemocyte primary culture and demonstrate appropriate immunological response, regulation and activity.
    Aquaculture 09/2015; 446. DOI:10.1016/j.aquaculture.2015.04.032 · 1.88 Impact Factor
  • Source
    • "However, little has been known about how IL-6 and other proinflammatory cytokines are regulated in EV71 infected patients. MAPK signaling pathways constitute key mediators of signal transduction from the cell surface to the nucleus (Roux and Blenis, 2004). Three prototype members of MAPK include the ERK1/2, p38, and the JNK1/2 or stress-activated protein kinase (SAPK), and regulate diverse cellular programs including embryogenesis and differentiation, cell proliferation, immune responses, and apoptosis (DeSilva et al., 1996; Dong et al., 2002; Wang et al., 2012). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Enterovirus 71 (EV71) has emerged as a clinically important neurotropic virus since poliovirus eradication. However, the mechanism of EV71induced neurological manifestation remains largely unclear. In this study, we showed that human astrocytes were susceptible to EV71 and viral RNA was first detected at 12 hr while viral proteins were detected at 36 hr post infection. EV71-infected astrocytes underwent apoptosis, in which cytochrome c was released from mitochondria to the cytosol and caspase-9 was activated. Interestingly during the infection caspase-2 and -8 were not cleaved or activated while a selective inhibitor of caspase-9, Z-LEHD-FMK, blocked the cleavage of caspase-3 and -7, indicating that only mitochondria-mediated intrinsic apoptotic pathway was activated in EV71-infected astrocytes. EV71 infection also induced proinflammatory cytokines, including IL-6, IL-8, CCL-5, and IP-10 in astrocytes, which may play a critical role in EV71-induced neuroinflammation and neurological complications. By using inhibitors of MAPKs, we demonstrated that the induction of the cytokines was mainly regulated by the MAP kinase p38 signaling pathway since when treated with p38 inhibitors, a significant reduction of the cytokines was observed. This study demonstrates that human astrocytes were susceptible to EV71 and the infection led to intrinsic apoptosis and induction of p38-regulated proinflammatory cytokines. These findings further our understanding of the neuropathogenesis in severe cases of EV71 infection.
    Journal of General Virology 07/2015; doi: 10.1099/jgv.0.000235(10). DOI:10.1099/jgv.0.000235 · 3.18 Impact Factor
  • Source
    • "Src kinase is a regulatory protein that participates in cell differentiation, migration and proliferation [31] [32]. ERK1/2, a member of the mitogen-activated protein kinase (MAPK) family, contributes to cell proliferation, migration, differentiation and apoptosis [33]. Inhibition of Src kinase and ERK1/2 can suppress lymphangiogenesis both in vitro and in vivo [34] [35]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Lymphangiogenesis, the formation of new lymph vessels, plays a significant role in the development and metastasis of various cancers. We and others have demonstrated that low molecular weight hyaluronan (LMW-HA) promotes lymphangiogenesis. However, the underlying mechanisms are poorly defined. In this study, using immunofluorescence and co-immunoprecipitation, we found that LMW-HA increased the colocalization of lymphatic vessel endothelial HA receptor (LYVE-1) and sphingosine 1-phosphate receptor (S1P3) at the cell surface. Silencing of either LYVE-1 or S1P3 decreased LMW-HA-mediated tube formation in lymphatic endothelial cells (LECs). Furthermore, silencing of either LYVE-1 or S1P3 significantly inhibited LMW-HA-induced tyrosine phosphorylation of Src kinase and extracellular signal-regulated kinase (ERK1/2). In summary, these results suggest that S1P3 and LYVE-1 may cooperate to play a role in LMW-HA-mediated lymphangiogenesis. This interaction may provide a useful target for the intervention of lymphangiogenesis-associated tumor progression. Copyright © 2015. Published by Elsevier Inc.
    Experimental Cell Research 06/2015; 14(1). DOI:10.1016/j.yexcr.2015.06.014 · 3.25 Impact Factor
Show more