Mechanism of inhibition of Raf-1 by protein kinase A.

Hafner, Susanne; Adler, Henric S.; Mischak, Harald; Janosch, Petra; Heidecker, Gisela; Wolfman, Alan; Pippig, Susanne; Lohse, Martin J.; Ueffing, Marius; Kölch, Walter

doi:10.1128/mcb.14.10.6696

Cited by 296 publications

(286 citation statements)

References 40 publications

Supporting

Mentioning

274

Contrasting

Order By: Relevance

“…However, in tumor cells, it is not known if stimulation of the b2AR can stimulate tumorigenesis. In some normal cells expressing B-Raf, b2ARs stimulate Erk1/2 by activating B-Raf which, in turn, activates Mek-1 (Erhardt et al, 1995;Vossler et al, 1997) whereas in other normal cells, b2ARs inactivate Erk1/2 by blocking Raf-1 (Hafner et al, 1994;Stork, 2001, 2002;Tortora and Ciardiello, 2002). Therefore, b2ARs may also inhibit or stimulate Erk1/2 and proliferation in tumors, and this may depend on the expression levels of not only the b2AR but also Raf-1 and/or B-Raf.…”

Section: Discussionmentioning

confidence: 99%

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

Carie

Sebti

2007

Oncogene

View full text Add to dashboard Cite

A chemical biology approach identifies a beta 2 adrenergic receptor (b2AR) agonist ARA-211 (Pirbuterol), which causes apoptosis and human tumor regression in animal models. b2AR stimulation of cAMP formation and protein kinase A (PKA) activation leads to Raf-1 (but not B-Raf) kinase inactivation, inhibition of Mek-1 kinase and decreased phospho-extracellular signal-regulated kinase (Erk)1/2 levels. ARA-211 inhibition of the Raf/ Mek/Erk1/2 pathway is mediated by PKA and not exchange protein activated by cAMP (EPAC). ARA-211 is selective and suppresses P-Erk1/2 but not P-JNK, P-p38, P-Akt or P-STAT3 levels. b2AR stimulation results in inhibition of anchorage-dependent and -independent growth, induction of apoptosis in vitro and tumor regression in vivo. b2AR antagonists and constitutively active Mek-1 rescue from the effects of ARA-211, demonstrating that b2AR stimulation and Mek kinase inhibition are required for ARA-211 antitumor activity. Furthermore, suppression of growth occurs only in human tumors where ARA-211 induces cAMP formation and decreases P-Erk1/2 levels. Thus, b2AR stimulation results in significant suppression of malignant transformation in cancers where it blocks the Raf-1/Mek-1/Erk1/2 pathway by a cAMP-dependent activation of PKA but not EPAC.

show abstract

Section: Discussionmentioning

confidence: 99%

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

Carie

Sebti

2007

Oncogene

View full text Add to dashboard Cite

show abstract

“…This regulation also seems to occur in i o, as the activity of BXB and v-Raf is down-regulated by PKA activation. Both mutants lack serines-43 and -259, and serine-621 is the only site that becomes phosphorylated in response to PKA activation [81,82]. However, other studies correlated serine-621 phosphorylation and 14-3-3 binding with an increase in activity [85].…”

Section: Making Connections : 14-3-3 Is At the Hubmentioning

confidence: 94%

“…Both sites are phosphorylated in resting cells [80], but can be hyperinduced by activation of PKA [81]. Replacing serine-621 with a number of other amino acids almost completely destroys the catalytic activity of Raf-1 and limits the usefulness of these mutants for activity studies [80,[82][83][84].…”

Section: Making Connections : 14-3-3 Is At the Hubmentioning

confidence: 99%

Meaningful relationships: the regulation of the Ras/Raf/MEK/ERK pathway by protein interactions

Kölch

2000

Biochemical Journal

1,040

118

View full text Add to dashboard Cite

The Ras\Raf\MEK (mitogen-activated protein kinase\ERK kinase)\ERK (extracellular-signal-regulated kinase) pathway is at the heart of signalling networks that govern proliferation, differentiation and cell survival. Although the basic regulatory steps have been elucidated, many features of this pathway are only beginning to emerge. This review focuses on the role of protein-protein interactions in the regulation of this pathway, INTRODUCTIONThe mitogen-activated protein kinase (MAPK) pathway is one of the primordial signalling systems that Nature has used in several permutations to accomplish an amazing variety of tasks. It exists in all eukaryotes, and controls such fundamental cellular processes as proliferation, differentiation, survival and apoptosis. The basic arrangement includes a G-protein working upstream of a core module consisting of three kinases : a MAPK kinase kinase (MAPKKK) that phosphorylates and activates a MAPK kinase (MAPKK), which in turn activates MAPK ( Figure 1). This set-up provides not only for signal amplification, but, maybe even more importantly, for additional regulatory interfaces that allow the kinetics, duration and amplitude of the activity to be precisely tuned. At present we can distinguish six MAPK modules, which share structurally related components, but seem to mediate specific biological responses. For recent reviews on MAPK pathways, the reader is referred to references [1][2][3]. Here we will focus on the regulation of the ERK (extracellular-signal-regulated kinase) pathway, which features Ras as G-protein, Raf as MAPKKK, MEK (MAPK\ERK kinase) as MAPKK and ERK as MAPK.Despite enjoying a decade in the limelight of scientific interest and revealing a plethora of new insights into the circuitry of signalling pathways in general, this pathway still holds many secrets. These pertain mainly to the regulation of Raf, and to a deeper understanding of how specific biological responses are encoded by spatial and temporal changes in the activity and subcellular distribution of the pathway components, and how these fluctuations are orchestrated at the molecular level. Work from many laboratories has highlighted protein-protein interactions as powerful means of co-ordinating signalling processes, most strikingly exemplified by the assembly of multi-protein signalling complexes on activated receptors, or of transcriptionfactor complexes on gene promoters. However, it is becoming Abbreviations used : Bcr, Breakpoint cluster region ; BXB, isolated Raf-1 kinase domain ; CNK, connector-enhancer of KSR ; CK2, casein kinase 2 ; CRD, cysteine-rich domain ; DEF, docking site for ERK, FxFP ; DLK, dual leucine-zipper-bearing kinase ; ERK, extracellular-signal-regulated kinase ; Hsp, heat-shock protein ; KIM, kinase interaction motif ; IκB, inhibitor of NF-κB ; JNK, c-Jun N-terminal kinase ; KSR, kinase suppressor of Ras ; MAPK, mitogen-activated protein kinase ; MAPKK, MAPK kinase ; MAPKKK, MAPK kinase kinase ; MEK, MAPK/ERK kinase ; MEKK, MEK kinase ; MP1, MEK partner 1 ; MUK, MAPK upstream kin...

show abstract

“…However, it has been shown that RafCT can still be regulated and overexpression of activated Src e ciently stimulates its Raf kinase activity (Haefner et al, 1994;Marais et al, 1995). As shown in Figure 3a RafCT kinase activity could be increased by MEK wt as well as MEK EE217/221 (14-and 11-fold, respectively), whereas activated Src F527 resulted in a 12.5-fold induction of RafCT kinase activity.…”

Section: Mek1 Mediated Hyperphosphorylation Of Raf-1 Correlates With mentioning

confidence: 96%

“…Ser259) and stimulation of Raf-1 kinase activity . It has been shown that protein kinase C can activate Raf-1 by phosphorylation of Ser499 (Kolch et al, 1993) whereas phosphorylation of Raf-1 by protein kinase A at Ser43 and Ser621 decreases Raf-1 kinase activity (Haefner et al, 1994;Mischak et al, 1996). In addition, stimulation of Raf-1 activity by cytokines involves phosphorylation on tyrosine residues (Turner et al, 1991).…”

Section: Introductionmentioning

confidence: 99%

MEK1 mediates a positive feedback on Raf-1 activity independently of Ras and Src

et al. 1997

View full text Add to dashboard Cite

Growth factor stimulated receptor tyrosine kinases activate a protein kinase cascade via the serine/threonine protein kinase Raf-1. Direct upstream activators of Raf-1 are Ras and Src. This study shows that MEK1, the direct downstream e ector of Raf-1, can also stimulate Raf-1 kinase activity by a positive feedback loop. Activated MEK1 mediates hyperphosphorylation of the amino terminal regulatory as well as of the carboxy terminal catalytic domain of Raf-1. The hyperphosphorylation of Raf-1 correlates with a change in the tryptic phosphopeptide pattern only at the carboxy terminus of Raf-1 and an increase in Raf-1 kinase activity. MEK1-mediated Raf-1 activation is inhibited by co-expression of the MAPK speci®c phosphatase MKP-1 indicating that the MEK1 e ect is exerted through a MAPK dependent pathway. Stimulation of Raf-1 activity by MEK1 is independent of Ras, Src and tyrosine phosphorylation of Raf-1. MEK1 can however synergize with Ras and leads to further increase of the Raf-1 kinase activity. Thus, MEK1 can mediate activation of Raf-1 by a novel positive feedback mechanism which allows fast signal ampli®cation and could prolong activation of Raf-1.

show abstract

Mechanism of inhibition of Raf-1 by protein kinase A.

Cited by 296 publications

References 40 publications

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

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

Meaningful relationships: the regulation of the Ras/Raf/MEK/ERK pathway by protein interactions

MEK1 mediates a positive feedback on Raf-1 activity independently of Ras and Src

Contact Info

Product

Resources

About