Phosphorylation of c-jun mediated by MAP kinases

Abstract

The proto-oncogene c-jun is a component of the AP-1 transcription factor family involved in the mediation of nuclear events elicited by extracellular stimuli. The c-jun protein is negatively regulated by phosphorylation of residues near the carboxy terminus which are dephosphorylated in response to phorbol esters. Here we identify two serine residues in the amino terminal A1 transactivation domain which are phosphorylated in response to a variety of mitogens, phorbol esters and activated ras. We present evidence that mitogen-activated protein-serine (MAP) kinases (pp54 and pp42/44) specifically phosphorylate these sites and that their phosphorylation positively regulates the transacting activity of c-jun. The MAP kinase enzymes pp54 and pp42/44 are regulated by tyrosine as well as serine/threonine phosphorylation. MAP kinase activation of c-jun may underlie the common stimulation of this transcription factor by mitogens, growth factors and oncogenes.

Elevated urokinase-type plasminogen activator receptor expression in a colon cancer cell line is due to a constitutively activated extracellular signal-regulated kinase-1-dependent signaling cascade

“…ERK1 increases c-Fos expression (Gille et al, 1992) which in turn up-regulates Fra-1 synthesis (Bergers et al, 1995). Additionally, there is evidence, albeit controversial, that indicates that the transactivating potential of cJun is increased by this MAPK (Pulverer et al, 1991;Agarwal et al, 1995;Bogoyevitch et al, 1995). We recently showed that the AP-1 motif at 7184, which was required for elevated u-PAR expression in RKO cells as well as the phorbol ester-inducible expression in GEO cells, was bound with c-Fos, Fra-1, and c-Jun (Lengyel et al, 1996).…”

“…Since all of these agents increase extracellular signal-regulated kinase (ERK) activity (Fabian et al, 1993;Bogoyevitch et al, 1994;Tsai et al, 1995), the objective of the current study was to determine the role of ERK1 and ERK2 in regulating u-PAR expression in these two colon cancer cell lines. The ERKs, which are mitogen-activated protein kinases (MAPKs), modulate the activity and/or synthesis of a diverse set of transcription factors involved in inducible gene expression (Gille et al, 1992;Rao and Reddy, 1993;Pulverer et al, 1991;Agarwal et al, 1995;Bogoyevitch et al, 1995;Janknecht, 1996;O'Hagan et al, 1996). These MAPKs are activated by phosphorylation on threonine and tyrosine residues by a dual activity kinase MEK1 (Crews et al, 1992).…”

MAPK signaling in neurodegeneration: influences of flavonoids and of nitric oxide

“…c-Jun is part of the activator protein-1 (AP-1) transcription factor, which either exists as Jun homodimer or as a Jun/Fos heterodimer [95]. The transcriptional activity of the AP-1 complex is increased [95] upon phosphorylation of Ser-63 and -73 of c-Jun by JNK [160]. In addition to c-Jun, JNKs also phosphorylate other AP-1 proteins, including JunB and JunD [25,95].…”

Signaling by dual specificity kinases

“…The phosphorylated ERKs activate other signaling proteins such as cPLA 2 (Nemeno et al, 1993;Lin et al, 1993) as well as other kinases (Boulton et al, 1991;Sturgill et al, 1988;Stokoe et al, 1992). In addition, the phosphorylated ERKs translocate to nucleus (Chen et al, 1992;Seth et al, 1992;Sanghera et al, 1992;Lenormand et al, 1993) where they activate transcription factors such as TCFs through phosphorylation (Alvarez et al, 1991;Pulverer et al, 1991;Baker et al, 1992;Gille et al, 1992) which leads to the activation of speci®c genes involved in cell proliferation (Davis, 1992;Johnson and Vaillancourt, 1994).…”