Inhibition of the EGF-Activated MAP Kinase Signaling Pathway by Adenosine 3′,5′-Monophosphate

Abstract

Mitogen-activated protein (MAP) kinases p42mapk and p44mapk are activated in cells stimulated with epidermal growth factor (EGF) and other agents. A principal pathway for MAP kinase (MAPK) activation by EGF consists of sequential activations of the guanine nucleotide exchange factor Sos, the guanosine triphosphate binding protein Ras, and the protein kinases Raf-1, MAPK kinase (MKK), and MAPK. Because adenosine 3',5'-monophosphate (cAMP) does not activate MAPK and has some opposing physiologic effects, the effect of increasing intracellular concentrations of cAMP with forskolin and 3-isobutyl-1-methylxanthine on the EGF-stimulated MAPK pathway was studied. Increased concentrations of cAMP blocked activation of Raf-1, MKK, and MAPK in Rat1hER fibroblasts, accompanied by a threefold increase in Raf-1 phosphorylation on serine 43 in the regulatory domain. Phosphorylation of Raf-1 in vitro and in vivo reduces the apparent affinity with which it binds to Ras and may contribute to the blockade by cAMP.

A chemical biology approach identifies a beta-2 adrenergic receptor agonist that causes human tumor regression by blocking the Raf-1/Mek-1/Erk1/2 pathway

“…Therefore, tumors that express two or more of these growth factors may require a cocktail of anticancer drugs. In contrast, b2AR stimulation will block activation of the Raf-1/Mek-1/Erk1/2 pathway when it is driven by several growth factors as they all require Mek to activate Erk1/2 (Graves et al, 1993;Sevetson et al, 1993;Wu et al, 1993;Sebolt-Leopold, 2000;Dumaz and Marais, 2005). For example, we have shown that growth factor (i.e., EGF) stimulation of P-Erk1/2 is blocked by ARA-211 in MDA-MB-231 cells (data not shown).…”

Regulation of cell proliferation by G proteins

“…However, it should be noted here that G s stimulates proliferation only in the cells ± such as those present in endocrine tissues ± that are positively responsive to cAMP-PKA signaling pathway for their cell growth. By contrast, in other cells, Ga s appears to have a growth inhibitory e ect through its negative regulation of Ras-Raf signaling pathway (Burgering et al, 1993;Graves et al, 1993;Cook and McCormick, 1993;Wu et al, 1993;Sevetson et al, 1993). In these cell types, PKA activated by Ga s through cAMP directly phosphorylates Raf at Ser 43 and/or Ser 671 Mischak et al, 1996) thus inhibiting Raf and its downstrean MEK-ERK cascade.…”

“…A case to the point is the ability of cAMP from G s signaling pathway to inhibit ERK-signaling pathway (Burgering et al, 1993;Graves et al, 1993;Cook and McCormick, 1993;Wu et al, 1993;Sevetson et al, 1993). Recently it has been shown that during genotoxic stress, p53, the well characterized tumor suppressor, downregulates the activity of Ga q and Ga 11 through Ga q/11 -speci®c RGS protein (Buckbinder et al, 1997), a negative regulator of G protein activity (Berman and Gilman, 1998).…”

Protein kinase A-Iα subunit-directed antisense inhibition of ovarian cancer cell growth: crosstalk with tyrosine kinase signaling pathway

“…It has been shown that PKA directly regulates the ras signaling pathway by phosphorylating raf-1 kinase (Wu et al, 1993;Cook and McCormick, 1993) and that the activated a-subunit of the heterotrimeric guanine nucleotide binding protein inhibits proliferative signals from ras through cAMP and PKA (Chen and Iyengar, 1994). In these mechanisms of action, an increase in intracellular cAMP levels is an essential prerequisite.…”