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)

Madin-Darby canine kidney (MDCK) epithelial cells transformed by oncogenic Ras and Raf exhibit cell multilayering and alterations in the actin cytoskeleton. The changes in the actin cytoskeleton comprise a loss of actin stress fibers and enhanced cortical actin. Using MDCK cells expressing a conditionally active form of Raf, we have explored the molecular mechanisms that underlie these observations. Raf activation elicited a robust increase in Rac1 activity consistent with the observed increase in cortical actin. Loss of actin stress fibers is indicative of attenuated Rho function, but no change in Rho-GTP levels was detected following Raf activation. However, the loss of actin stress fibers in Raf-transformed cells was preceded by the induced expression of Rnd3, an endogenous inhibitor of Rho protein function. Expression of Rnd3 alone at levels equivalent to those observed following Raf transformation led to a substantial loss of actin stress fibers. Moreover, cells expressing activated RhoA failed to multilayer in response to Raf. Pharmacological inhibition of MEK activation prevented all of the biological and biochemical changes described above. Consequently, the data are consistent with a role for induced Rnd3 expression downstream of the Raf-MEK-extracellular signal-regulated kinase pathway in epithelial oncogenesis.
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PMID:Induced expression of Rnd3 is associated with transformation of polarized epithelial cells by the Raf-MEK-extracellular signal-regulated kinase pathway. 1109 87

The actin cytoskeleton controls multiple cellular functions, including cell morphology, movement, and growth. Accumulating evidence indicates that oncogenic activation of the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase 1/2 (MEK/ERK1/2) pathway is accompanied by actin cytoskeletal reorganization. However, the signaling events contributing to actin cytoskeleton remodeling mediated by aberrant ERK1/2 activation are largely unknown. Mutant B-RAF is found in a variety of cancers, including melanoma, and it enhances activation of the MEK/ERK1/2 pathway. We show that targeted knockdown of B-RAF with small interfering RNA or pharmacological inhibition of MEK increased actin stress fiber formation and stabilized focal adhesion dynamics in human melanoma cells. These effects were due to stimulation of the Rho/Rho kinase (ROCK)/LIM kinase-2 signaling pathway, cumulating in the inactivation of the actin depolymerizing/severing protein cofilin. The expression of Rnd3, a Rho antagonist, was attenuated after B-RAF knockdown or MEK inhibition, but it was enhanced in melanocytes expressing active B-RAF. Constitutive expression of Rnd3 suppressed the actin cytoskeletal and focal adhesion effects mediated by B-RAF knockdown. Depletion of Rnd3 elevated cofilin phosphorylation and stress fiber formation and reduced cell invasion. Together, our results identify Rnd3 as a regulator of cross talk between the RAF/MEK/ERK and Rho/ROCK signaling pathways, and a key contributor to oncogene-mediated reorganization of the actin cytoskeleton and focal adhesions.
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PMID:B-RAF regulation of Rnd3 participates in actin cytoskeletal and focal adhesion organization. 1804 87

Forkhead transcription factor, Foxd3, plays a critical role during development by controlling the lineage specification of neural crest cells. Notably, Foxd3 is highly expressed during the wave of neural crest cell migration that forms peripheral neurons and glial cells but is downregulated prior to migration of cells that give rise to the melanocytic lineage. Melanoma is the deadliest form of skin cancer and is derived from melanocytes. Recently, we showed that FOXD3 expression is elevated following the targeted inhibition of the B-RAF-MEK (MAP/ERK kinase)-ERK (extracellular signal-regulated kinase)1/2 pathway in mutant B-RAF melanoma cells. Because melanoma cells are highly migratory and invasive in a B-RAF-dependent manner, we explored the role of FOXD3 in these processes. In this study, we show that ectopic FOXD3 expression inhibits the migration, invasion, and spheroid outgrowth of mutant B-RAF melanoma cells. Upregulation of FOXD3 expression following inhibition of B-RAF and MEK correlates with the downregulation of Rnd3, a Rho GTPase and inhibitor of RhoA-ROCK signaling. Indeed, expression of FOXD3 alone was sufficient to downregulate Rnd3 expression at the mRNA and protein levels. Mechanistically, FOXD3 was found to be recruited to the Rnd3 promoter. Inhibition of ROCK partially restored migration in FOXD3-expressing cells. These data show that FOXD3 expression downregulates migration and invasion in melanoma cells and Rnd3, a target known to be involved in these properties.
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PMID:FOXD3 regulates migration properties and Rnd3 expression in melanoma cells. 2147 67