Pro-inflammatory Cytokines and Environmental Stress Cause p38 Mitogen-activated Protein Kinase Activation by Dual Phosphorylation on Tyrosine and Threonine

Abstract

Protein kinases activated by dual phosphorylation on Tyr and Thr (MAP kinases) can be grouped into two major classes: ERK and JNK. The ERK group regulates multiple targets in response to growth factors via a Ras-dependent mechanism. In contrast, JNK activates the transcription factor c-Jun in response to pro-inflammatory cytokines and exposure of cells to several forms of environmental stress. Recently, a novel mammalian protein kinase (p38) that shares sequence similarity with mitogen-activated protein (MAP) kinases was identified. Here, we demonstrate that p38, like JNK, is activated by treatment of cells with pro-inflammatory cytokines and environmental stress. The mechanism of p38 activation is mediated by dual phosphorylation on Thr-180 and Tyr-182. Immunofluorescence microscopy demonstrated that p38 MAP kinase is present in both the nucleus and cytoplasm of activated cells. Together, these data establish that p38 is a member of the mammalian MAP kinase group.

Tiam1 is involved in the regulation of bufalin-induced apoptosis in human leukemia cells

“…Another member of the mitogen-activated protein kinase (MAPK) family, p38, was ®rst identi®ed as a protein that is phosphorylated at a tyrosine residue upon treatment of murine pre-B cells with lipopolysaccharide (LPS) (Han et al, 1993). Further studies have shown that p38 is activated in response to hyperosmolarity and mediators of inflammation, such as interleukin-1 (IL-1) and tumor necrosis factor a (TNF-a) (Han et al, 1994;Raingeaud et al, 1995). Both JNK and p38 are activated during apoptosis that is induced by various environmental stresses, such as heat shock, osmotic stress and UV light (Xia et al, 1995;Raingeaud et al, 1995;Galcheva-Gargova et al, 1994;Kyriakis and Avruch, 1996).…”

“…Further studies have shown that p38 is activated in response to hyperosmolarity and mediators of inflammation, such as interleukin-1 (IL-1) and tumor necrosis factor a (TNF-a) (Han et al, 1994;Raingeaud et al, 1995). Both JNK and p38 are activated during apoptosis that is induced by various environmental stresses, such as heat shock, osmotic stress and UV light (Xia et al, 1995;Raingeaud et al, 1995;Galcheva-Gargova et al, 1994;Kyriakis and Avruch, 1996). The withdrawal of NGF from cultures of PC12 cells leads to activation of JNK and p38 and inhibition of ERK (Xia et al, 1995).…”

Activation and signaling of the p38 MAP kinase pathway

“…Many transcription factors encompassing a broad range of action have been shown to be phosphorylated and subsequently activated by p38. Examples include activating transcription factor 1, 2 & 6 (ATF-1/2/6), SRF accessory protein (Sap1), CHOP (growth arrest and DNA damage inducible gene 153, or GADD153), p53, C/EBPβ, myocyte enhance factor 2C (MEF2C), MEF2A, MITF1, DDIT3, ELK1, NFAT, and high mobility group-box protein 1 (HBP1) [17,55,[66][67][68][69][70][71][72][73][74][75][76]] . An important cis-element, AP-1 appears to be influenced by p38 through several different mechanisms.…”

Induction of erythroid differentiation by inhibition of Ras/ERK pathway in a Friend murine leukemia cell line

“…We also analysed the phosphorylation pro®les of another member of the MAPK family, p38, which was recently found to be activated transiently in response to EPO (Nagata et al, 1997). Activation of p38 is known to occur through phosphorylation of threonine-180 and tyrosine-182 (Raingeaud et al, 1995), and this can also be monitored by similar immunoblot assay. In the ras17N-expressing cells, however, only gradual decrease in the levels of total p38 protein as well as its phosphorylated form was observed ( Figure 4b).…”