KSR, a novel protein kinase required for RAS signal transduction

Therrien, Marc; Chang, Henry; Solomon, Noah M.; Karim, Felix D.; Wassarman, David A.; Rubin, Gerald M.

doi:10.1016/0092-8674(95)90204-x

Cited by 352 publications

(364 citation statements)

References 38 publications

Supporting

Mentioning

342

Contrasting

Unclassified

Order By: Relevance

“…PKCa has also been shown to increase the kinase activity of Raf-1 in the cell-free system (Kolch et al, 1993), although it is not clear whether PKC is involved in the Ras-dependent Raf-1 activation. Ksr-1 was originally identi®ed as a suppressor of abnormal phenotype induced by an activated mutant of Ras in both Drosophila (Therrien et al, 1995) and Caenorhabditis elegans (Kornfeld et al, 1995;Sundaram and Han, 1995). Since Ksr-1 associates with Raf-1 in a Rasdependent manner (Therrien et al, 1996), it may also be a candidate for a cytosolic Raf-1 activator.…”

Section: Discussionmentioning

confidence: 99%

Isolation of a new protein factor required for activation of Raf-1 by Ha-Ras: partial purification from rat brain cytosols

1998

View full text Add to dashboard Cite

Ras-mediated signaling pathways play a critical role in cellular proliferation and di erentiation. Although it has been demonstrated that Ras interacts with Raf-1 to stimulate the serine/threonine kinase activity of Raf-1, the precise mechanism by which Ras activates Raf-1 remains obscure. To address this question, we developed a cell-free system in which the activated form of H-Ras can induce Raf-1 activation. Using this system, we found the presence of a new protein factor, in cytosolic fractions of both human embryonic kidney 293 cells and rat brain tissues, that is required for Ras-dependent activation of Raf-1. The factor was puri®ed from rat brain cytosols through successive column chromatographies on DEAE Sephacel, SP Sepharose and Sephacryl S-300. The approximate molecular weight of the activator was estimated as 400 000 by gel ®ltration. Its activity was sensitive to heat and trypsin treatments. The puri®ed activator did not contain Src, 14-3-3, protein kinase C, JAK2 or Ksr-1, as judged by immunoblotting. Further characterization of the activator is underway.

show abstract

Section: Discussionmentioning

confidence: 99%

Isolation of a new protein factor required for activation of Raf-1 by Ha-Ras: partial purification from rat brain cytosols

1998

View full text Add to dashboard Cite

show abstract

“…These include the effectors Rain1 on the Golgi and the activated Raf-MEK-ERK cascade on endosomes [83,84]. Further examples include scaffolds for the Raf-MAPK cascade; whilst KSR is recruited to the cell surface, Sef is localised on the Golgi and p14-MP1 on endosomes [85][86][87][88].…”

Section: Compartmentalised Ras Signallingmentioning

confidence: 99%

Ras proteins: paradigms for compartmentalised and isoform-specific signalling

Omerovic

Laude

Prior

2007

Cell. Mol. Life Sci.

117

122

View full text Add to dashboard Cite

Ras GTPases mediate a wide variety of cellular processes by converting a multitude of extracellular stimuli into specific biological responses including proliferation, differentiation and survival. In mammalian cells, three ras genes encode four Ras isoforms (H-Ras, K-Ras4A, KRas4B and N-Ras) that are highly homologous but functionally distinct. Differences between the isoforms, including their post-translational modifications and intracellular sorting, mean that Ras has emerged as an important model system of compartmentalised signalling and membrane biology. Ras isoforms in different subcellular locations are proposed to recruit distinct upstream and downstream accessory proteins and activate multiple signalling pathways. Here, we summarise data relating to isoform specific signalling, its role in disease and the mechanisms promoting compartmentalised signalling. Further understanding of this field will reveal the role of Ras signalling in development, cellular homeostasis and cancers and may suggest new therapeutic approaches.

show abstract

“…Recently, we reported that an auxiliary member of the Raf-MAPK signaling pathway, kinase suppressor of Ras-1 (KSR-1) (Therrien et al, 1995;Zhang et al, 1997), is upregulated at both mRNA and protein level in 1,25D-treated HL60 cells, and when KSR-1 upregulation is reduced by an antisense strategy differentiation of these cells is inhibited. Conversely, transfection of a fulllength KSR-1 expression construct potentiated HL60 cell differentiation induced by near-physiological levels of 1,25D (Wang and Studzinski, 2004).…”

Section: Introductionmentioning

confidence: 99%

Induction of kinase suppressor of RAS-1(KSR-1) gene by 1, α25-dihydroxyvitamin D3 in human leukemia HL60 cells through a vitamin D response element in the 5′-flanking region

Wang

White

et al. 2006

Oncogene

View full text Add to dashboard Cite

Differentiation therapy is being developed as an additional therapeutic option for the treatment of several forms of cancer, including myeloid leukemia. In model systems, the physiologically active form of vitamin D, 1, a25-dihydroxyvitamin D 3 (1,25D), induces monocytic differentiation of human myeloid cells, but the mechanism is not clear. We report here, the first direct connection between the signal provided by 1,25D and the molecular circuitry known to be involved in monocytic differentiation. Specifically, we show that 1,25D selectively increases the expression of the gene encoding kinase suppressor of Ras-1 (KSR-1) in HL60 cells, while other differentiationinducing agents such as 12-O-tetradecanoylphorbol-13-acetate, retinoic acid or dimethyl sulfoxide do not significantly increase KSR-1 expression. Further, the upregulation of KSR-1 gene by 1,25D is competed by ZK159222, an antagonist of vitamin D receptor (VDR) action, and can occur in the presence of protein synthesis inhibitor cycloheximide, showing that the effect is direct. Most importantly, we have identified a vitamin D responsive element (VDRE) in the promoter region of the human KSR-1 gene, to which VDR binds in a 1,25D-dependent manner, in vitro and in vivo. This binding is paralleled by increased association of RNA polymerase II with the transcription start site of KSR-1 gene, and the VDRE is functional in reporter assays. Our findings offer a potential mechanism for a signaling pathway that contributes to 1,25D-induced monocytic differentiation of human myeloid leukemia cells.

show abstract

KSR, a novel protein kinase required for RAS signal transduction

Cited by 352 publications

References 38 publications

Isolation of a new protein factor required for activation of Raf-1 by Ha-Ras: partial purification from rat brain cytosols

Isolation of a new protein factor required for activation of Raf-1 by Ha-Ras: partial purification from rat brain cytosols

Ras proteins: paradigms for compartmentalised and isoform-specific signalling

Induction of kinase suppressor of RAS-1(KSR-1) gene by 1, α25-dihydroxyvitamin D3 in human leukemia HL60 cells through a vitamin D response element in the 5′-flanking region

Contact Info

Product

Resources

About