EMBO J 2006,
PMID: 16810323
Pardo, Olivier E; Wellbrock, Claudia; Khanzada, Umme K; Aubert, Muriel; Arozarena, Imanol; Davidson, Sally; Bowen, Frances; Parker, Peter J; Filonenko, V V; Gout, Ivan T; Sebire, Neil; Marais, Richard; Downward, Julian; Seckl, Michael J
Patients with small cell lung cancer (SCLC) die because of chemoresistance. Fibroblast growth factor-2 (FGF-2) increases the expression of antiapoptotic proteins, XIAP and Bcl-X(L), and triggers chemoresistance in SCLC cells. Here we show that these effects are mediated through the formation of a specific multiprotein complex comprising B-Raf, PKCepsilon and S6K2. S6K1, Raf-1 and other PKC isoforms do not form similar complexes. RNAi-mediated downregulation of B-Raf, PKCepsilon or S6K2 abolishes FGF-2-mediated survival. In contrast, overexpression of PKCepsilon increases XIAP and Bcl-X(L) levels and chemoresistance in SCLC cells. In a tetracycline-inducible system, increased S6K2 kinase activity triggers upregulation of XIAP, Bcl-X(L) and prosurvival effects. However, increased S6K1 kinase activity has no such effect. Thus, S6K2 but not S6K1 mediates prosurvival/chemoresistance signalling.
Diseases/Pathways annotated by Medline MESH: Carcinoma, Small Cell, Lung Neoplasms
Document information provided by NCBI PubMed
Text Mining Data
XIAP → Fibroblast growth factor-2 (FGF-2): "
Fibroblast growth factor-2 (FGF-2) increases the expression of antiapoptotic proteins,
XIAP and Bcl-X ( L ), and triggers chemoresistance in SCLC cells
"
XIAP → S6K2: "
In a tetracycline-inducible system, increased S6K2 kinase activity triggers upregulation of XIAP , Bcl-X ( L ) and prosurvival effects
"
Manually curated Databases
-
IRef Biogrid Interaction:
MAP2K1
—
BRAF
(direct interaction, enzymatic study)
-
IRef Biogrid Interaction:
RPS6KB2
—
BRAF
(direct interaction, enzymatic study)
-
IRef Biogrid Interaction:
RPS6KB2
—
BRAF
(physical association, affinity chromatography technology)
-
IRef Biogrid Interaction:
RPS6KB2
—
PRKCE
(physical association, affinity chromatography technology)
-
IRef Biogrid Interaction:
PRKCE
—
BRAF
(physical association, affinity chromatography technology)
-
IRef Hprd Interaction:
RPS6
—
RPS6KB2
(in vitro)
-
IRef Hprd Interaction:
RPS6
—
RPS6KB1
(in vitro)
-
IRef Hprd Interaction:
MAP2K1
—
BRAF
(in vivo)
-
IRef Hprd Interaction:
MAP2K1
—
BRAF
(in vitro)
-
IRef Hprd Interaction:
PRKCE
—
MAPK3
(in vivo)
-
IRef Hprd Interaction:
PRKCE
—
RPS6KB2
(in vivo)
-
IRef Hprd Interaction:
PRKCE
—
BRAF
(in vivo)
-
IRef Hprd Interaction:
Complex of PRKCE-BRAF-PRKCE-BRAF-RPS6KB2-BRAF-PRKCE-RPS6KB2-RPS6KB2
(in vivo)
-
IRef Intact Interaction:
RPS6KB2
—
RPS6
(phosphorylation reaction, protein kinase assay)
-
IRef Intact Interaction:
PRKCA
—
BRAF
(physical association, anti bait coimmunoprecipitation)
-
IRef Intact Interaction:
RPS6KA2
—
PRKCE
(physical association, anti bait coimmunoprecipitation)
-
IRef Intact Interaction:
MAP3K1
—
BRAF
(phosphorylation reaction, protein kinase assay)
-
IRef Intact Interaction:
RPS6KA2
—
BRAF
(physical association, anti bait coimmunoprecipitation)
-
IRef Intact Interaction:
RPS6KA2
—
RPS6
(phosphorylation reaction, protein kinase assay)
-
IRef Intact Interaction:
RPS6KA2
—
PRKCA
(physical association, anti bait coimmunoprecipitation)
-
IRef Intact Interaction:
PRKCE
—
BRAF
(physical association, anti bait coimmunoprecipitation)
-
IRef Intact Interaction:
PRKCE
—
PRKCA
(physical association, anti bait coimmunoprecipitation)
In total, 14 gene pairs are associated to this article in curated databases