The Signal-Dependent Coactivator CBP Is a Nuclear Target for pp90RSK

Abstract

We have examined the mechanism by which growth factor-mediated induction of the Ras pathway interferes with signaling via the second messenger cAMP. Activation of cellular Ras with insulin or NGF stimulated recruitment of the S6 kinase pp90RSK to the signal-dependent coactivator CBP. Formation of the pp90RSK-CBP complex occurred with high stoichiometry and persisted for 6-8 hr following growth factor addition. pp90RSK specifically recognized the E1A-binding domain of the coactivator CBP. In addition, like E1A, binding of pp90RSK to CBP was sufficient to repress transcription of cAMP-responsive genes via the cAMP-inducible factor CREB. By contrast with its effects on the cAMP pathway, formation of the pp90RSK-CBP complex was required for induction of Ras-responsive genes. These results provide a demonstration of cross-coupling between two signaling pathways that occurs at the level of a signal-dependent coactivator.

The 90-kDa Ribosomal S6 Kinase (pp90rsk) Phosphorylates the N-terminal Regulatory Domain of IκBα and Stimulates Its Degradation in Vitro

“…pp90 rsk Triggers Degradation of I B␣ in Vitropp90 rsk Phosphorylates I B␣ by pp90 rsk Principally on Serine 32-Previous in vivo studies have shown that both S32 and S36 at the N terminus of I B␣ are required for signal-induced phosphorylation and degradation of this inhibitor (7)(8)(9)(10)18). Additionally, both of these serine residues are directly phosphorylated in vivo by an unknown kinase(s) following cellular stimulation with PMA or TNF-␣ (45). Phosphorylation at these sites in vivo results in a slower electrophoretic mobility for the I B␣ protein that is readily detectable on SDS-PAGE gels.…”

“…pp90 rsk Triggers Degradation of I B␣ in Vitropp90 rsk2 , one of three closely related rsk genes (rsk1, rsk2, rsk3), has been shown to function as a stimulus-coupled CREB kinase modulating CREB activity by phosphorylating this factor on a key regulatory serine located at position 133 (44). Conversely, pp90 rsk appears to oppose CREB action by inducibly but stably associating with the CREB-binding protein and blocking the interaction of this co-activator with CREB (45). Of note, the enzymatic function of pp90 rsk is not required for these latter inhibitory effects.…”

Critical role for Rsk2 in T-lymphocyte activation

“…23,24 Rsk family kinases have multiple cellular functions. They are involved in the phosphorylation of histone H3 and remodeling of chromatin in response to epidermal growth factor (EGF) 25 and can regulate gene expression by phosphorylating transcription factors, including c-Fos, 26,27 cAMP-response element-binding protein (CREB), [28][29][30] CREB-binding protein, 31,32 estrogen receptor, 33 ATF4,34 NFATc4, 35 and NF-B/I B␣. 36,37 p90 Rsk2 was also reported to phosphorylate the p34 cdc2 inhibitory kinase Myt1 in frog oocytes, leading to activation of the cyclin-dependent kinase p34 cdc2 that then promotes cell-cycle progression of oocytes through the G2/M phase of meiosis.…”

ICER-IIγ is a tumor suppressor that mediates the antiproliferative activity of cAMP

“…The nuclear events by which cAMP exerts such growth-inhibitory e ect remain largely undetermined (Xing et al, 1996;Nakajima et al, 1996). In the nucleus the cAMP pathway uses cAMP-responsive element binding proteins to mediate gene expression (reviewed by Habener, 1990;Vallejo, 1994;Molina, 1997).…”