Multiple Mitogen-Activated Protein Kinase Signaling Pathways Connect the Cot Oncoprotein to the c-junPromoter and to Cellular Transformation

Abstract

The serine/threonine kinase Cot is a member of the mitogen-activated protein kinase (MAPK) kinase kinase family implicated in cellular transformation. Enhanced expression of this protein has been shown to activate both the MAPK and the c-Jun N-terminal kinase (JNK) pathways and to stimulate the nuclear factor of activated T cells and NF-B-dependent transcription. However, the nature of the normal functions of the Cot protein and the molecular mechanisms responsible for its oncogenic potential are still largely unknown. Here, we show that overexpression of the cot proto-oncogene is sufficient to stimulate the expression of c-jun and that, in turn, the activity of c-Jun is required for Cot-induced transformation. These observations prompted us to explore the molecular events by which Cot regulates c-jun expression. We found that Cot potently stimulates the activity of the c-jun promoter utilizing JNK-dependent and -independent pathways, the latter involving two novel members of the MAPK family, p38␥ (ERK6) and ERK5. Molecularly, this activity was found to be dependent on the ability of Cot to activate, in vivo, members of each class of the MAPK kinase superfamily, including MEK, SEK, MKK6, and MEK5. Furthermore, the use of dominant interfering molecules revealed that Cot requires JNK, p38s, and ERK5 to stimulate the c-jun promoter fully and to induce neoplastic transformation. These findings indicate that Cot represents the first example of a serine/threonine kinase acting simultaneously on all known MAPK cascades. Moreover, these observations strongly suggest that the transforming ability of Cot results from the coordinated activation of these pathways, which ultimately converge on the regulation of the expression and activity of the product of the c-jun proto-oncogene.

Regulation and function of TPL-2, an IκB kinase-regulated MAP kinase kinase kinase

“…Consistent with this hypothesis, TPL-2 overexpression in COS-7 and 3T3 cells activates ERK, JNK, p38γ and ERK5 MAP kinases [18][19][20]. Immunoprecipitated TPL-2 phosphorylates MEK-1, MKK-4 (also known as SEK-1), MEK-5 and MKK-6, suggesting that TPL-2 functions directly as a MAP3 kinase [19,20]. This was subsequently confirmed using recombinant TPL-2 purified from lysates of baculovirus-infected insect cells and recombinant MEK protein as a substrate [21].…”

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

“…Recent reports from loss-of-function studies demonstrate that MKK4 is also required for ultraviolet radiation-induced activation of p38 MAPK (Brancho et al, 2003). At higher upstream levels, numerous MAP3Ks including MEKK, ASK, TAK1, Tpl-2/Cot and MLK/DAK have been implicated in the p38 activation (Yamaguchi et al, 1995;Tibbles et al,1996;Ichijo et al,1997;Deacon et al,1999;Chiariello et al, 2000). 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).…”

Aberrant expression of extracellular signal-regulated kinase 5 in human prostate cancer

“…Its unique C-terminal tail contains a myocyte enhancer factor 2 (MEF2)-interacting domain and a potent transcriptional activation domain (Kasler et al, 2000). The activity of several transcriptional factors has been shown to be regulated by ERK5, including MEF2, c-Fos and Fra-1, Sap-1, c-Myc and nuclear factor-kB (Kato et al, 1997;English et al, 1998;Kamakura et al, 1999;Chiariello et al, 2000;Terasawa et al, 2003). It plays a key role in embryogenesis: ERK5 knockout mice embryos die between day 9.5 and 11.5 due to severe cardiovascular defects (Regan et al, 2002;Sohn et al, 2002) whereas mice lacking ERK1 develop normally (Pages et al, 1999;Selcher et al, 2001).…”