Role of p38 and JNK Mitogen-Activated Protein Kinases in the Activation of Ternary Complex Factors

Abstract

The transcription factors Elk-1 and SAP-1 bind together with serum response factor to the serum response element present in the c-fos promoter and mediate increased gene expression. The ERK, JNK, and p38 groups of mitogen-activated protein (MAP) kinases phosphorylate and activate Elk-1 in response to a variety of extracellular stimuli. In contrast, SAP-1 is activated by ERK and p38 MAP kinases but not by JNK. The proinflammatory cytokine interleukin-1 (IL-1) activates JNK and p38 MAP kinases and induces the transcriptional activity of Elk-1 and SAP-1. These effects of IL-1 appear to be mediated by Rho family GTPases. Transcription of the prototypic immediate-early gene c-fos is rapidly induced in cells treated with a wide variety of extracellular stimuli, including growth factors, cytokines, UV radiation, and phorbol ester. The serum response element (SRE) is an important regulatory sequence located in the c-fos promoter (75) and is a target for a number of signal transduction pathways (7,8,81). The SRE is recognized by a complex of serum response factor (SRF) and a ternary complex factor (TCF) (76).SRF is phosphorylated in vitro by casein kinase II, the ERKactivated S6 kinase p90 rsk , and a DNA-activated protein kinase (8). However, the role of these kinases in the transcriptional activation of SRF remains unclear. Calcium activates SRFdependent transcription independently of TCF, by a mechanism involving Ca 2ϩ /calmodulin-dependent protein kinases (51). A recent study has provided evidence that members of the Ras-related Rho family of GTPases are involved in signaling pathways that lead to SRF-mediated activation of the c-fos SRE independently of complex formation with TCFs (27). This family of GTPases includes Cdc42, Rac1, and RhoA. These GTPases play a critical role in regulating the actin cytoskeleton and other physiological processes (60). RhoA is important for SRF-mediated induction of the c-fos SRE by serum, lysophosphatidic acid, and aluminum fluoride (27). Activated mutants of Cdc42 and Rac1 have been proposed to stimulate SRFmediated transcription independently of TCFs (27). The signaling mechanisms involved in these events await elucidation.TCF proteins belong to a subgroup of the Ets domain family (33) that includes Elk-1 (28), SAP-1 (13), and SAP-2 (21, 44, 54). The primary sequences of these proteins show significant similarity in three distinct regions (76). The N-terminal 93 amino acids comprise the Ets domain, which mediates DNA binding (13,32,70). The more centrally located 21-amino-acid B box is required for ternary complex formation and has been demonstrated to mediate direct protein-protein contacts between Elk-1 and SRF (69). The COOH-terminal activation domain contains several conserved mitogen-activated protein (MAP) kinase phosphorylation sites (76). Phosphorylation of the TCF proteins Elk-1 and SAP-1 on sites within the Cterminal activation domain results in activated SRE-dependent gene expression (7,8,81).MAP kinases are proline-directed Ser/Thr protein kinases that are regulated by ...

Stimulation of urokinase-type plasminogen activator receptor expression by PMA requires JNK1-dependent and -independent signaling modules

“…The increased binding of c-Fos to the AP-1 motif in PMA-treated OVCAR-3 cells was also evident. This could represent stimulation of c-Fos expression by way of phosphorylation and activation of Elk-1 or Sap-1a (Whitmarsh et al, 1997;Janknecht and Hunter, 1997) by JNK1. Alternatively, this could be a result of a parallel stimulation of the classical c-Raf-1-ERK pathway by PMA leading to increased c-Fos expression via the phosphorylation of p62 TCF (Gille et al, 1992).…”

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.…”

Caenorhabditis elegans mom-4 is required for the activation of the p38 MAPK signaling pathway in the response to Pseudomonas aeruginosa infection

“…Our previous results have pointed out the complexity of the MAP kinase signaling pathway, which is due to the fact that each individual MAP kinase can be activated by two or three upstream MAP2Ks and multiple MAP3Ks in Drosophila under different stimuli (Zhuang et al, 2006). Upon activation, p38 can phosphorylate and activate a number of transcription factors including ATF-2/ATF-7, CHOP/GADD153, Elk1, MEF2-C, Sap1 and CREB (Wang et al,1996;Raingeaud et al,1996;Han et al,1997;Iordanov et al,1997;Whitmarsh et al,1997;Shivers et al, 2010), and protein kinases such as MAPKAPK2, MNK, PRAK, MSK1 and RSK-B (Stokoe et al,1992;Fukunaga et al,1997;Waskiewicz et al,1997;New et al,1998;Deak et al,1998;Pierrat et al,1998), thus eliciting different cellular responses.…”