Coupling of the RAS-MAPK Pathway to Gene Activation by RSK2, a Growth Factor-Regulated CREB Kinase

  title={Coupling of the RAS-MAPK Pathway to Gene Activation by RSK2, a Growth Factor-Regulated CREB Kinase},
  author={Jun Xing and David D. Ginty and Michael Eldon Greenberg},
  pages={959 - 963}
A signaling pathway has been elucidated whereby growth factors activate the transcription factor cyclic adenosine monophosphate response element-binding protein (CREB), a critical regulator of immediate early gene transcription. Growth factor-stimulated CREB phosphorylation at serine-133 is mediated by the RAS-mitogen-activated protein kinase (MAPK) pathway. MAPK activates CREB kinase, which in turn phosphorylates and activates CREB. Purification, sequencing, and biochemical characterization of… 
Nerve Growth Factor Activates Extracellular Signal-Regulated Kinase and p38 Mitogen-Activated Protein Kinase Pathways To Stimulate CREB Serine 133 Phosphorylation
Findings indicate that NGF activates two distinct MAPK pathways, both of which contribute to the phosphorylation of the transcription factor CREB and the activation of immediate-early genes.
Cell survival promoted by the Ras-MAPK signaling pathway by transcription-dependent and -independent mechanisms.
The findings suggest that the MAPK signaling pathway promotes cell survival by a dual mechanism comprising the posttranslational modification and inactivation of a component of the cell death machinery and the increased transcription of pro-survival genes.
CREB: a stimulus-induced transcription factor activated by a diverse array of extracellular signals.
The molecular mechanisms by which Ser133-phosphorylated CREB activates transcription, intracellular signaling pathways that lead to phosphorylation ofCREB at Ser133, and features of each signaling pathway that impart specificity at the level of CREB activation are discussed.
CREB phosphorylation at Ser133 regulates transcription via distinct mechanisms downstream of cAMP and MAPK signalling.
It is shown that embryonic fibroblasts from the S133A-knockin mice show that Ser133 phosphorylation downstream of PKA is required for CBP/p300 recruitment, and MSK-mediated CREB phosphorylated is critical for the induction of CREB-dependent genes downstream of MAPK signalling.
A Protein Kinase C-, Ras-, and RSK2-dependent Signal Transduction Pathway Activates the cAMP-responsive Element-binding Protein Transcription Factor following T Cell Receptor Engagement*
Experiments are consistent with a model in which TCR engagement leads to the rapid phosphorylation and activation of CREB via a signaling pathway involving the activation of p56 lck, PKC, Ras, Raf-1, MEK, and RSK2.
Hypoxia Induces Phosphorylation of the Cyclic AMP Response Element-binding Protein by a Novel Signaling Mechanism*
A physiological reduction in O2 levels induces a functional phosphorylation of CREB at Ser133 via a novel signaling pathway, more robust than that induced by any other stimulus tested, including forskolin, depolarization, and osmotic stress.
The Mitogen-Activated Protein Kinase Cascade Couples PKA and PKC to cAMP Response Element Binding Protein Phosphorylation in Area CA1 of Hippocampus
An unexpected richness of diversity in the regulation of MAPK in the hippocampus is observed and the possibility of a broad role for the MAPK cascade in regulating gene expression in long-term forms of hippocampal synaptic plasticity is suggested.
Transcription Factor Phosphorylation by pp90 rsk2
The in vitro phosphorylation of transcription factors by growth factor-activated protein kinases has resulted in the discovery of a number of activities whose identities and relationships to one another are unclear, and Fos kinase and NGFI-B kinase I and pp90 rsk2 represent the same protein kinase species.
Mitogen- and Stress-Activated Protein Kinase 1 Mediates cAMP Response Element-Binding Protein Phosphorylation and Activation by Neurotrophins
It is shown here that neurotrophin-induced CREB phosphorylation in CNS neurons depends exclusively on the extracellular signal-regulated kinase 1/2-activated kinase mitogen- and stress-activated protein kinases 1 (MSK1).


Nuclear localization and regulation of erk- and rsk-encoded protein kinases.
In vitro studies raise the possibility that the MAP kinase/RSK signal transduction pathway represents a protein-Tyr/Ser/Thr phosphorylation cascade with the spatial distribution and temporal regulation that can account for the rapid transmission of growth-regulating information from the membrane, through the cytoplasm, and to the nucleus.
A growth factor-induced kinase phosphorylates the serum response factor at a site that regulates its DNA-binding activity
A model in which the growth factor-induced phosphorylation of SRF contributes to the activation of c-fos transcription by facilitating the formation of an active transcription complex at the serum response element is suggested.
Serine 133-Phosphorylated CREB Induces Transcription via a Cooperative Mechanism That May Confer Specificity to Neurotrophin Signals
Results indicate that CREB is a versatile transcription factor that activates transcription via distinct mechanisms in a stimulus-specific manner and that by selectively activating delayed response genes, CREB may confer specificity to neurotrophin signals that promote the survival and differentiation of neurons.
Phosphorylation of the c-Fos transrepression domain by mitogen-activated protein kinase and 90-kDa ribosomal S6 kinase.
Evidence is provided that two growth-regulated, nucleus- and cytoplasm-localized protein kinases, 90-kDa ribosomal S6 kinase (RSK and MAP kinase), contribute to the serum-induced phosphorylation of c-Fos.
Phosphorylation of transcription factor p62TCF by MAP kinase stimulates ternary complex formation at c-fos promoter
It is shown that p62TCF is phosphorylated by MAP kinase in vitro and that phosphorylation results in enhanced ternary complex formation, linking the expression of the human c-fos proto-oncogene to signal transduction pathways known to be activated before its own induction.
The MAPK signaling cascade
  • R. Seger, E. Krebs
  • Biology
    FASEB journal : official publication of the Federation of American Societies for Experimental Biology
  • 1995
This review highlights primarily the first MAPK cascade to be discovered that uses the MEK and ERK isoforms and describes their involvement in different cellular processes, and it is now known that signaling pathways initiated by phorbol esters, iono‐phors, heat shock, and liganda for seven transmembrane receptors use distinct MAPK cascades with little or no cross‐reactivity between them.
Activation of ternary complex factor Elk‐1 by MAP kinases.
It is demonstrated that recombinant Elk‐1 is hyperphosphorylated in vivo upon joint overexpression ofMAPKs and constitutively activated Raf‐1 kinase, the latter serving as an indirect in vivo activator of MAPKs.
Calcium activates serum response factor-dependent transcription by a Ras- and Elk-1-independent mechanism that involves a Ca2+/calmodulin-dependent kinase
Findings indicate that SRF is a versatile transcription factor that, when bound to the SRE, can function by distinct mechanisms and can mediate transcriptional responses to both CaMK- and Ras-dependent signaling pathways.