Relations between the mitogen-activated protein kinase and the cAMP-dependent protein kinase pathways: Comradeship and hostility

Gerits, Nancy; Kostenko, Sergiy; Shiryaev, Alexey; Johannessen, Mona; Moens, Ugo

doi:10.1016/j.cellsig.2008.02.022

Cited by 161 publications

(135 citation statements)

References 200 publications

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“…Fourth, we have revealed that in the ovarian cancer cell line OVCAR3, the proliferation-relevant βAR-PKA signaling axis (24,47) is linked to Rac-PAK-Erk1/2-mediated activation of the transcription factor Elk1. Overall our findings disclose a unique crossroad of frequently targeted receptor cascades (RTK, βAR) that integrates cAMP responses and GTPase activities spatially and temporally, leading to modulation of the crucial Raf-Mek-Erk signaling axis (11)(12)(13)(14)(15)(16). It has been described that PKA activities regulate GEFs and GAPs that change the GTP loading of Rac1, resulting in changes of signaling related to morphological alterations of the cytoskeleton (48)(49)(50).…”

Section: Discussionmentioning

confidence: 99%

“…9 and 10). It has been long regarded that the GPCR-cAMP-PKA signaling axis participates, among others, in the regulation of cell growth, differentiation, and motility (9)(10)(11)(12)(13). Such fundamental cellular functions are controlled by mitogenic signals that are transmitted through cascades involving crucially regulated mitogen-activated protein kinases (MAPK) like Erk1/2 (14).…”

mentioning

confidence: 99%

“…It has been described that the Rho GTPase Ras-related C3 botulinum toxin substrate 1 (Rac1) participates in the regulation of transformation, growth, and survival of tumor cells at least partially by controlling extracellular signal-regulated kinase (Erk)1/2 activation (15,16). So far, several functionally diverse means have been illustrated how hormone-triggered cAMP pulses participate in the regulation and transmission of mitogenic signals originating from RTK via the Raf-Mek-Erk pathway (11)(12)(13). At different stages of RTK-mediated signal transmission, these pathways interact to regulate proliferation.…”

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confidence: 99%

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Reciprocal regulation of PKA and Rac signaling

Bachmann

Riml

Huber

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Activated G protein-coupled receptors (GPCRs) and receptor tyrosine kinases relay extracellular signals through spatial and temporal controlled kinase and GTPase entities. These enzymes are coordinated by multifunctional scaffolding proteins for precise intracellular signal processing. The cAMP-dependent protein kinase A (PKA) is the prime example for compartmentalized signal transmission downstream of distinct GPCRs. A-kinase anchoring proteins tether PKA to specific intracellular sites to ensure precision and directionality of PKA phosphorylation events. Here, we show that the Rho-GTPase Rac contains A-kinase anchoring protein properties and forms a dynamic cellular protein complex with PKA. The formation of this transient core complex depends on binary interactions with PKA subunits, cAMP levels and cellular GTP-loading accounting for bidirectional consequences on PKA and Rac downstream signaling. We show that GTP-Rac stabilizes the inactive PKA holoenzyme. However, β-adrenergic receptor-mediated activation of GTP-Rac-bound PKA routes signals to the Raf-Mek-Erk cascade, which is critically implicated in cell proliferation. We describe a further mechanism of how cAMP enhances nuclear Erk1/2 signaling: It emanates from transphosphorylation of p21-activated kinases in their evolutionary conserved kinase-activation loop through GTPRac compartmentalized PKA activities. Sole transphosphorylation of p21-activated kinases is not sufficient to activate Erk1/2. It requires complex formation of both kinases with GTP-Rac1 to unleash cAMP-PKA-boosted activation of Raf-Mek-Erk. Consequently GTPRac functions as a dual kinase-tuning scaffold that favors the PKA holoenzyme and contributes to potentiate Erk1/2 signaling. Our findings offer additional mechanistic insights how β-adrenergic receptor-controlled PKA activities enhance GTP-Rac-mediated activation of nuclear Erk1/2 signaling. signal transduction | cross-talk S ignal transduction cascades coordinate the plethora of extracellular stimuli into biological responses within cells. The specificity of receptor-initiated signaling responses is encoded by spatial and temporal dynamics of downstream signaling networks (1). These networks, initiating from e.g., the G protein-coupled receptor (GPCR) superfamily and receptor tyrosine kinases (RTK), tightly regulate signaling pathways at several critical points via feedback loops and cross-talk among other pathways (2-5). A large number of GPCR signaling cascades uses cAMP as an intracellular second messenger (3, 6). In response to hormone binding to distinct GPCRs, cAMP is produced and binds to its canonical effector, the cAMP-dependent protein kinase A (PKA). cAMP binding to the PKA regulatory subunits (R) induces dissociation of the tetrameric PKA holoenzyme, resulting in active PKA catalytic subunits (PKAc; Fig. 1C) (7, 8). To ensure substrate specificity, PKA is tethered to distinct subcellular compartments through physical interaction with A-kinase anchoring proteins (AKAPs; refs. 9 and 10). It has been long regarded that the...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Reciprocal regulation of PKA and Rac signaling

Bachmann

Riml

Huber

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Gerits et al (27) suggested that cAMP/PKA-dependent inhibition of ERK is mediated by raf-1, and that PKA-induced activation of ERK is interceded through B-raf. PKA and B-raf mediate ERK activation by thyrotropin (TSH) to stimulate thyroid cell stimulation (28).…”

Section: Discussionmentioning

confidence: 99%

cAMP antagonizes ERK-dependent antiapoptotic action of insulin

Cui

Hong²,

Guan³

et al. 2011

BMB Reports

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“…Strong evidence suggests that PKA directly phosphorylates Ser259 (10,26) , whereas Akt seems to have a direct as well as an indirect effect (27 -29) . Recent reports have indicated that PKA can phosphorylate additional regulatory Raf-1 residues; Ser43, whose phosphorylation interferes with binding to Ras, and Ser233, whose phosphorylation in addition to that of Ser259, enhances the binding of 14-3-3 and suppresses the catalytic activity of Raf (30) . Raf membrane recruitment also facilitates its association with other proteins involved in the activation process that stabilize the open and active conformation of Raf.…”

Section: Ras-dependent Activation Of Raf Kinasementioning

confidence: 99%

Raf kinases in signal transduction and interaction with translation machinery

Migliaccio

Sanges

Ruggiero

et al. 2013

BioMolecular Concepts

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Abstract:In recent years, a large amount of evidence has given a central role to translational control in diseases such as cancer, tissue hypertrophy and neurodegeneration. Its deregulation can directly modulate cell cycling, transformation and survival response. The aim of this review is to describe the interaction between Raf activation and the main characters of the translational machinery, such as the elongation factor 1A (eEF1A), which has been recognized in recent years as one of the most interesting putative oncogenes. A particular emphasis is given to an intriguing non-canonical role that eEF1A can play in the relationship between the Ras → Raf-1 → MEK1 → ERK-1/2 and PI3K → Akt signaling pathways. Recently, our group has described a C-Raf kinase-mediated phosphorylation of eEF1A triggered by a survival pathway induced upon interferon alpha (IFN α ) treatment in the human epidermoid cancer cell line (H1355). This phosphorylation seems to be the center of the survival pathway that counteracts the well-known pro-apoptotic function of IFN α . Furthermore, we have identified two new phosphorylation sites on eEF1A (Ser21 and Thr88) that are substrates for Raf kinases in vitro and, likely, in vivo as well. These residues seem to have a significant functional role in the control of cellular processes, such as cell proliferation and survival. In fact, overexpression of eEF1A2 in gemcitabine-treated cancer cells caused the upregulation of phosphoAkt and an increase in cell viability, thereby suggesting that eEF1A2 could exert its oncogenic behavior by participating in the regulation of PI3K pathway.

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Relations between the mitogen-activated protein kinase and the cAMP-dependent protein kinase pathways: Comradeship and hostility

Cited by 161 publications

References 200 publications

Reciprocal regulation of PKA and Rac signaling

Reciprocal regulation of PKA and Rac signaling

cAMP antagonizes ERK-dependent antiapoptotic action of insulin

Raf kinases in signal transduction and interaction with translation machinery

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