The ins and outs of Raf kinases

Daum, Günter; Eisenmann-Tappe, Iris; Fries, Hans-Werner; Troppmair, Jakob; Rapp, Ulf R.

doi:10.1016/0968-0004(94)90133-3

Cited by 491 publications

(376 citation statements)

References 27 publications

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“…Involvement of PKC in the regulation of cell growth is well established [19,20] and in C6 cells PKC activity changes with different stages of the cell cycle being highest in Go [21]. However, the role of individual PKC subspecies in the regulation of cell growth is poorly understood [6][7][8] though PKC ~ is a RAF-1 kinase [4] which provides one route to activation of certain early response genes. Here we show that PKC activity and protein expression of the ~ and ~ subspecies of PKC increases as C6 cells become growth-arrested by contact inhibition in the presence of serum while protein expression of the y and e subspecies decreases, these subspecies being barely detected in contact-inhibited quiescent C6 cells.…”

Section: Discussionmentioning

confidence: 99%

“…The mitogenic effect of growth factors and phorbol esters is mediated through the protein kinase C (PKC) family of phospholipid-dependent serine/threonine kinases [1,2] which can activate proliferation-associated genes via Raf and the MAP kinase pathway [3,4]. The twelve subspecies of PKC identified to date fit into three main groups, the conventional (c) PKC subspecies c~, fl~,/3, and ~" requiring calcium and diacylglycerol (DAG), the novel (n) calcium-independent PKC subspecies ~, e, r/, ~t and 0 activated by DAG and the atypical (a) subspecies 5, t and 2 being both calcium and DAG independent [5].…”

Section: Introductionmentioning

confidence: 99%

“…phosphorylation [4]. Over-expression of c and n group PKC subspecies in cells causes contrasting effects on growth rate and cell morphology (summarised in [6,7]) while the downregulation-sensitive PKC subspecies (cz,/3, 6, e) regulate cyclin-dependent kinases in endothelial cells [8].…”

Section: Introductionmentioning

confidence: 99%

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Protein expression of the α, γ, δ and ε subspecies of protein kinase C changes as C6 glioma cells become contact inhibited and quiescent in the presence of serum

et al. 1995

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Total protein kinase C (PKC) activity and protein expression of the c~ and 6 subspecies of PKC increases markedly as C6 glioma cells grow from low cell density to the contactinhibited quiescent state (also known as Go) in the presence of serum. At the same time protein expression of PKC subspecies y and e decreases while the iBl, ~ID t and ~ subspecies did not change. Serum deprivation of growing C6 glioma cells does not induce the same changes in PKC subspecies protein expression. The findings support the growing view that there are significant differences between the Go states brought about by contact inhibition or serum deprivation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Protein expression of the α, γ, δ and ε subspecies of protein kinase C changes as C6 glioma cells become contact inhibited and quiescent in the presence of serum

et al. 1995

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“…Activation of growth factor receptors stimulates a variety of parallel signal transduction cascades (reviewed in Daum et al, 1994;Slupsky et al, 1998). The best understood signalling pathway is the classic cytoplasmic cascade, which regulates cell proliferation and di erentiation and leads to activation of ERK-1 and ERK-2 (Rapp, 1991;Blenis, 1993;Daum et al, 1994;Slupsky et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

“…The best understood signalling pathway is the classic cytoplasmic cascade, which regulates cell proliferation and di erentiation and leads to activation of ERK-1 and ERK-2 (Rapp, 1991;Blenis, 1993;Daum et al, 1994;Slupsky et al, 1998). Mammalian ERKs are activated by phosphorylation on a threonine and a tyrosine residue in a conserved TEY motif by the dual speci®city protein kinases MEK-1 and MEK-2 (Crews and Erikson, 1992;Cano and Mahadevan, 1995).…”

Section: Introductionmentioning

confidence: 99%

Cot protooncoprotein activates the dual specificity kinases MEK-1 and SEK-1 and induces differentiation of PC12 cells

1999

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Mitogenic signals initiated at the plasma membrane are transmitted to the nucleus through an intricate signalling network. We identi®ed the protooncoprotein Cot as a new component of mitogenic signalling cascades, which activates both the classic cytoplasmic cascade and the SAPK stress pathway. Wildtype and activated Cot phosphorylate and activate MEK-1 and SEK-1 in vitro. These ®ndings are consistent with the sequence homology between Cot and the rat gene Tpl-2. Expression of oncogenic Cot in 293, NIH3T3 and PC12 cells leads to in vivo phosphorylation of endogenous c-Jun and Erk-1/2 suggesting that the serine/threonine kinase Cot functions beside c-Raf-1 and Mos as a direct activator of MEK-1. Furthermore, we have examined the biological e ects of Cot on the phenotype of ®broblastic and neuronal cells. In order to test a potential c-Raf-1 dependency of Cot transformation, the e ect of oncogenic Cot on Raf revertant CHP25 cells was determined. Cot could restore the transformed phenotype indicating that Cot transformation is not dependent on active c-Raf-1 and that Cot is not a target for the putative Raf inhibitor, which is presumably active in the revertant cell line. Expression of oncogenic versions of Raf as well as v-Mos leads to di erentiation of PC12 cells. Cot also induces neurite outgrowth of PC12 cells. These data are consistent with the role of Cot in the classic mitogenic cascade and suggest that the simultaneously activated JNK/SAPK stress pathway has no antagonistic e ects in this context.

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Molecular dynamics simulations of the Ras:Raf and Rap:Raf complexes

1999

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The protein Raf is an immediate downstream target of Ras in the MAP kinase signalling pathway. The complex of Ras with the Ras-binding domain (RBD) of Raf has been modelled by homology to the (E30D,K31E)-Rap1A:RBD complex, and both have been subjected to multiple molecular dynamics simulations in solution. While both complexes are stable, several rearrangements occur in the Ras:RBD simulations: the RBD loop 100-109 moves closer to Ras, Arg73 in the RBD moves towards Ras to form a salt bridge with Ras-Asp33, and Loop 4 of the Ras switch II region shifts upwards toward the RBD. The Ras:RBD interactions (including the RBD-Arg73 interaction) are consistent with available NMR and mutagenesis data on the Ras: RBD complex in solution. The Ras switch II region does not interact directly with the RBD, although indirect interactions exist through the effector domain and bridging water molecules. No large-scale RBD motion is seen in the Ras:RBD complex, compared to the Rap:RBD complex, to suggest an allosteric activation of Raf by Ras. This may be because the Raf kinase domain (whose structure is unknown) is not included in the model.

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The ins and outs of Raf kinases

Cited by 491 publications

References 27 publications

Protein expression of the α, γ, δ and ε subspecies of protein kinase C changes as C6 glioma cells become contact inhibited and quiescent in the presence of serum

Protein expression of the α, γ, δ and ε subspecies of protein kinase C changes as C6 glioma cells become contact inhibited and quiescent in the presence of serum

Cot protooncoprotein activates the dual specificity kinases MEK-1 and SEK-1 and induces differentiation of PC12 cells

Molecular dynamics simulations of the Ras:Raf and Rap:Raf complexes

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