A synthetic inhibitor of the mitogen-activated protein kinase cascade.
TLDR
Results indicate that the MAPK pathway is essential for growth and maintenance of the ras-transformed phenotype and PD 098059 is an invaluable tool that will help elucidate the role of theMAPK cascade in a variety of biological settings.Abstract:
Treatment of cells with a variety of growth factors triggers a phosphorylation cascade that leads to activation of mitogen-activated protein kinases (MAPKs, also called extracellular signal-regulated kinases, or ERKs). We have identified a synthetic inhibitor of the MAPK pathway. PD 098059 [2-(2'-amino-3'-methoxyphenyl)-oxanaphthalen-4-one] selectively inhibited the MAPK-activating enzyme, MAPK/ERK kinase (MEK), without significant inhibitory activity of MAPK itself. Inhibition of MEK by PD 098059 prevented activation of MAPK and subsequent phosphorylation of MAPK substrates both in vitro and in intact cells. Moreover, PD 098059 inhibited stimulation of cell growth and reversed the phenotype of ras-transformed BALB 3T3 mouse fibroblasts and rat kidney cells. These results indicate that the MAPK pathway is essential for growth and maintenance of the ras-transformed phenotype. Further, PD 098059 is an invaluable tool that will help elucidate the role of the MAPK cascade in a variety of biological settings.read more
Citations
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Specificity and mechanism of action of some commonly used protein kinase inhibitors
TL;DR: The results demonstrate that the specificities of protein kinase inhibitors cannot be assessed simply by studying their effect on kinases that are closely related in primary structure, and proposes guidelines for the use of protein Kinase inhibitors in cell-based assays.
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Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions.
Gray W. Pearson,Fred L. Robinson,Tara Beers Gibson,Bing E. Xu,Mahesh Karandikar,Kevin S. Berman,Melanie H. Cobb +6 more
TL;DR: Nonenzymatic mechanisms that impact MAP kinase functions and findings from gene disruption studies are highlighted and particular emphasis is on ERK1/2.
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PD 098059 Is a Specific Inhibitor of the Activation of Mitogen-activated Protein Kinase Kinase in Vitro and in Vivo
TL;DR: The results indicate that the activation of Raf is suppressed and that its inactivation is accelerated by a downstream component(s) of the MAP kinase pathway.
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Functional expression cloning of nanog, a pluripotency sustaining factor in embryonic stem cells
Ian Chambers,Douglas Colby,Morag Robertson,Jennifer Nichols,Sonia Lee,Susan Tweedie,Austin Smith +6 more
TL;DR: These findings establish a central role for Nanog in the transcription factor hierarchy that defines ES cell identity and confirm that Cytokine dependence, multilineage differentiation, and embryo colonization capacity are fully restored upon transgene excision.
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Targeting RAS signalling pathways in cancer therapy
TL;DR: The RAS proteins control signalling pathways that are key regulators of several aspects of normal cell growth and malignant transformation and are aberrant in most human tumours.
References
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Activation of MAP kinase kinase is necessary and sufficient for PC12 differentiation and for transformation of NIH 3T3 cells
TL;DR: Results show that, depending on cellular context, activation of MAP kinase kinase is necessary and sufficient for cell differentiation or proliferation.
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Mammalian Ras interacts directly with the serine/threonine kinase Raf
TL;DR: Raf interacts with wild-type and activated Ras, but not with an effector domain mutant of Ras or with a dominant-interfering Ras mutant, and this interaction is dependent on GTP bound to Ras.
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A novel kinase cascade triggered by stress and heat shock that stimulates MAPKAP kinase-2 and phosphorylation of the small heat shock proteins.
John Rouse,Philip Cohen,Sylviane Trigon,Michel Morange,Ana Alonso-Llamazares,Daniel Zamanillo,Tim Hunt,Angel R. Nebreda +7 more
TL;DR: The RKK, RK, and MAPKAP kinase-2 constitute a new stress-activated signal transduction pathway in vertebrates that is distinct from the classical MAPK cascade.
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Transformation of mammalian cells by constitutively active MAP kinase kinase
Sam J. Mansour,W. T. Matten,April S. Hermann,Julian M. Candia,Sing Rong,Kenji Fukasawa,G F Vande Woude,Natalie G. Ahn +7 more
TL;DR: It is found that constitutive activation of MAPKK is sufficient to promote cell transformation and is associated with highly tumorigenic in nude mice.
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A divergence in the MAP kinase regulatory network defined by MEK kinase and Raf
TL;DR: MEKK was expressed in all mouse tissues tested, and it phosphorylated and activated MEK, independent of Raf, a growth factor-regulated protein kinase that also phosphorylates MEK.