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| In brief: October 2002Cell signalling
The ankyrin repeat protein Diversin recruits Casein kinase IE to the This study describes a new vertebrate protein — Diversin — that is an essential component of the Wnt signalling pathway. Diversin acts as a molecular switch. It inhibits signals mediated by the canonical Wnt/ Cell signalling
A family of Rhomboid intramembrane proteases activates all Drosophila membrane-tethered EGF ligands.
Keren, a new ligand of the Drosophila epidermal growth factor receptor, undergoes two modes of cleavage.
In the first of two papers that highlight the Drosophila EGF receptor (DER) pathway, Urban et al. investigated the processing of the DER ligands Spitz, Gurken and Keren. Rhomboid-1 is involved in the activation of Spitz by proteolytic cleavage, and analysis of four members of the Rhomboid family showed that Rhomboids 1–4 can proteolytically activate all three DER ligands. This common cleavage mechanism is distinct from that used to activate mammalian EGF-like ligands. In the second paper, Reich and Shilo describe the previously uncharacterized DER ligand Keren. Although Keren is processed as described above, proteolytic activation can also occur in a Rhomboid-independent manner, which highlights the complex regulation of this signalling pathway. Genetic screening
High-throughput retroviral tagging to identify components of specific signalling pathways in cancer.
This paper, together with two more letters in the September issue of Nature Genetics, describes the first in vivo mammalian genetic screens used to identify genes underlying human cancer. Mikkers et al. show the power of using retroviral insertional mutagenesis, together with the complete mouse genome sequence, by identifying genes that can substitute for Pim1 and Pim2 in lymphomagenesis. This strategy is the mammalian equivalent of the powerful yeast, D. melanogaster and C. elegans genetic screens. Oncogenes
RAF/RAS oncogenes and mismatch-repair status.
Activating mutations in a member of the RAF family, BRAF, have been found in a high proportion of melanomas and in other cancers. Rajagopalan et al. report that BRAF mutations in colorectal cancers occur only in tumours that do not carry mutations in KRAS, and that mutations in BRAF are linked to the ability of these tumours to repair mismatch bases in DNA. These results indicate that mutations in BRAF and KRAS exert equivalent effects in tumorigenesis. Oncogenes
Distinct requirements for Ras oncogenesis in human versus mouse cells.
Oncogenic Ras stimulates three main classes of effector proteins — Rafs, PI3-kinase and RalGEFs — with Rafs generally being the most potent at transforming mouse cells. However, using oncogenic Ras mutants, Hamad et al. found that RalGEF is sufficient for Ras transformation in human cells. The findings indicate that signal-transduction biochemistry studies in mice might have to be revisited to assess applicability to humans, and that RalGEF could be a promising target for anti cancer therapies. Technology
New genes involved in cancer identified by retroviral tagging.
High-throughput retroviral tagging to identify components of specific signalling pathways in cancer.
Genome-wide retroviral insertional tagging of genes involved in cancer in Cdkn2a-deficient mice.
Three groups report here that a modification of the invertebrate suppressor/enhancer screen can be used successfully in mammals. To demonstrate this, they infected mice already mutant at certain loci — loci that are known to cause lymphomas — with Moloney murine leukemia virus, which accelerates and exacerbates lymphoma formation. The resulting tumours were screened for common insertion sites (CISs) that were then cloned and compared against the assembled mouse genome sequence to identify the disrupted loci. The screen yielded many known and novel loci that synergize with the initial mutation to bring about tumorigenesis. Because each group started with a different mouse mutant, most of the obtained CISs were unique, but common loci (mostly genes involved in cell proliferation and differentiation) were also recovered, validating the specificity of this approach. Inflammatory diseases
The role of prostaglandin E2 receptors in the pathogenesis of rheumatoid arthritis.
Prostaglandin E2 — which can act through at least four different G-protein-coupled receptors, EP1–EP4 — has been implicated in rheumatoid arthritis. Mice that lack the EP4 receptor show decreased incidence and severity of disease in a model of rheumatoid arthritis, but this is not the case in mice that lack either EP1, EP2 or EP3, indicating that EP4 might represent a novel and specific therapeutic target. Anticancer drugs
Medulloblastoma growth inhibition by Hedgehog pathway blockade.
There are no effective treatments for medulloblastoma, the most common malignant brain tumour in children. Using cyclopamine — a known antagonist of a protein involved in the Hedgehog signalling pathway — Berman et al. show that the pathway is important for the growth of medulloblastoma cells and is therefore a potential target for therapeutic intervention. | | |||||||||
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-catenin degradation complex and acts in both canonical Wnt and Wnt/JNK signaling.
