Disease relevance of ksr

• In contrast, papilloma formation in Tg.AC mice, resulting from skin-specific v-Ha-ras expression, was completely abrogated in the ksr1-/- background [1].

High impact information on ksr

• Together, these findings identify a novel protein complex that controls RAF activation and suggest that KSR does not only act as a scaffold for the MAPK (mitogen-activated protein kinase) module, but may also function as a RAF activator [2].
• Here, we show that KSR functions upstream of MEK within the ERK/MAPK module [3].
• One of these is Kinase Suppressor of Ras (KSR), a component previously identified in RAS-dependent genetic screens in Drosophila and Caenorhabditis elegans [3].
• In agreement with this, we found that KSR facilitates the phosphorylation of MEK by RAF [3].
• The isolated KSR kinase domain suppressed Xenopus oocyte maturation, cellular transformation, and Drosophila eye development, suggesting that separation of the amino- and carboxy-terminal domains has uncoupled the normal regulation of KSR as a positive effector of Ras signaling [4].

Biological context of ksr

• We screened approximately 185,000 mutagenized progeny for dominant modifiers of the KSR-dependent rough eye phenotype [5].
• While biochemical evidence suggests that the role of KSR is closely linked to the signal transduction mechanism of the MAPK cascade, the precise molecular function of KSR remains unresolved [5].
• Overexpression of the KSR kinase domain in a subset of cells during Drosophila eye development blocks photoreceptor cell differentiation and results in the external roughening of the adult eye [5].
• Loss-of-function mutations in the genes encoding RAF, MEK, MAPK and KSR dominantly suppress RAS1V12-induced cell proliferation [6].
• These data indicate that KSR is a potent modulator of a signaling pathway essential to normal and oncogenic cell growth and development [7].

Anatomical context of ksr

• The growth of MT-driven mammary tumor was moderately slowed in ksr1-/- mice, however, consistent with a decreased rate of proliferation of ksr1-/- cells (T cells and embryonic fibroblasts) [1].
• We examined the effect of mammalian KSR expression on the activation of extracellular ligand-regulated (ERK) mitogen-activated protein (MAP) kinase in fibroblasts [7].

Associations of ksr with chemical compounds

• Treatment of cells with geldanamycin, an inhibitor of HSP90, decreases the half-life of KSR, suggesting that HSPs may serve to stabilize KSR [8].

Regulatory relationships of ksr

• Reduction of either yan or ttk activity suppresses eye phenotypes of the kinase suppressor of ras (ksr) gene mutation, which is consistent with the involvement of yan and ttk in the Ras/MAPK pathway [9].

Other interactions of ksr

• By analogy to catalytically impaired, but conformationally active B-RAF oncogenic mutants, we discuss the possibility that KSR represents a natural allosteric inducer of RAF catalytic function [2].
• CNK is required for membrane recruitment of Raf, while KSR is likely required to couple Raf to upstream kinases [10].
• The nucleotide variation at total sites (pi(t)) ranged from 0.0013 in the ksr, to 0.0173 in the Adh [11].

References