Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.12.2 (MEK)
 18,161 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

SWAP-70, a phosphatidylinositol trisphosphate (PtdIns(3,4,5)P(3)) binding protein, has been suggested to be involved in transformation of mouse embryo fibroblasts (MEFs) as well as membrane ruffling after growth factor stimulation of the cells. A mutant, SWAP-70-374, was found to be able to bind to F-actin in vitro, whereas wild-type SWAP-70 failed to do so. This mutant was present at the plasma membrane without any stimulation while the wild-type protein was present only in the cytosol unless cells were stimulated with EGF. Expression of this mutant in MEFs resulted in morphologic transformation, fast growth, and loss of contact inhibition, suggesting that SWAP-70 with this mutation can transform the cells. ERK1/2 was activated in SWAP-70-374-transformed cells. Use of MEK inhibitors revealed that the ERK1/2 pathway does not affect the cell growth of MEFs but is responsible for loss of contact inhibition. To investigate the function of SWAP-70 further, drugs that can inhibit SWAP-70-dependent cell responses were screened. Among various drugs, sanguinarine was found to inhibit transformation of MEFs by SWAP-70-374. This drug was able to inhibit SWAP-70-mediated membrane ruffling as well, suggesting that its effect was closely related to the SWAP-70 signaling pathway. These results suggest that SWAP-70-374 can activate some signaling pathways, including the ERK1/2 pathway, to transform MEFs.
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PMID:A mutant of SWAP-70, a phosphatidylinositoltrisphosphate binding protein, transforms mouse embryo fibroblasts, which is inhibited by sanguinarine. 2115 38

SWAP-70 is a protein that has been suggested to be involved in regulation of actin rearrangement. Having discovered that an artificially-derived mutant of SWAP-70 can transform mouse embryo fibroblasts, we searched for naturally-occurring mutations in the SWAP-70 gene, finding listings for several on the Web at www.sanger.ac.uk/genetics/CGP/cosmic/, including three mutations found in ovarian cancers. (The number of such mutations has now reached 13 out of 228 tumors). We created expression vectors for the mutant SWAP-70 proteins and introduced these into NIH3T3 cells. The cells expressing the mutant SWAP-70 constructs exhibited faster growth than the parental or wild-type SWAP-70-expressing cells. In most instances, cells that are able to grow in soft agar will form tumors in nude mice. While SWAP-70-transformed cells grew in soft agar, they failed to form tumors in nude mice. This result implies that transformation by the SWAP-70 mutants is unique. The cells bearing the mutant SWAP-70 genes were sensitive to nutrient starvation, supporting the idea that they are transformed cells. However, they failed to pile up and demonstrated contact inhibition, unlike most normal transformed cells. Upon expression of human SWAP-70 genes, MEK1 was activated. This activation appeared to contribute to the saturation density of the cells. As SWAP-70 has been shown to be the last protein to receive signals from cytokines, it is likely that there is a putative feedback signaling pathway, and that disorder of this signaling pathway can transform cells. Accordingly, this may explain why SWAP-70-transformed cells have different characteristics than most transformed cells.
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PMID:SWAP-70: a new type of oncogene. 2355 4