PD 098059 has been shown previously to inhibit the dephosphorylated form of mitogen-activated protein kinase kinase-1 (MAPKK1) and a mutant MAPKK1(S217E,S221E), which has low levels of constitutive activity (Dudley, D. T., Pang, L., Decker, S. J., Bridges, A. J., and Saltiel, A. R.(1995) Proc. Natl. Acad. Sci. U. S. A. 92, 7686-7689). Here we report that PD 098059 does not inhibit Raf-activated MAPKK1 but that it prevents the activation of MAPKK1 by Raf or MEK kinase in vitro at concentrations (IC = 2-7 µM) similar to those concentrations that inhibit dephosphorylated MAPKK1 or MAPKK1(S217E,S221E). PD 098059 inhibited the activation of MAPKK2 by Raf with a much higher IC value (50 µM) and did not inhibit the phosphorylation of other Raf or MEK kinase substrates, indicating that it exerts its effect by binding to the inactive form of MAPKK1. PD 098059 also acts as a specific inhibitor of the activation of MAPKK in Swiss 3T3 cells, suppressing by 80-90% its activation by a variety of agonists. The high degree of specificity of PD 098059 in vitro and in vivo is indicated by its failure to inhibit 18 protein Ser/Thr kinases (including two other MAPKK homologues) in vitro by its failure to inhibit the in vivo activation of MAPKK and MAP kinase homologues that participate in stress and interleukin-1-stimulated kinase cascades in KB and PC12 cells, and by lack of inhibition of the activation of p70 S6 kinase by insulin or epidermal growth factor in Swiss 3T3 cells. PD 098059 (50 µM) inhibited the activation of p42 and isoforms of MAP kinase-activated protein kinase-1 in Swiss 3T3 cells, but the extent of inhibition depended on how potently c-Raf and MAPKK were activated by any particular agonist and demonstrated the enormous amplification potential of this kinase cascade. PD 098059 not only failed to inhibit the activation of Raf by platelet-derived growth factor, serum, insulin, and phorbol esters in Swiss 3T3 cells but actually enhanced Raf activity. The rate of activation of Raf by platelet-derived growth factor was increased 3-fold, and the subsequent inactivation that occurred after 10 min was prevented. These 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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				M. Kidd, I. M. Modlin, G. N. Eick, R. L. Camp, and S. M. Mane Role of CCN2/CTGF in the proliferation of Mastomys enterochromaffin-like cells and gastric carcinoid development Am J Physiol Gastrointest Liver Physiol, January 1, 2007; 292(1): G191 - G200. [Abstract] [Full Text] [PDF]

				J. Tsai, W. Qiu, R. Kohen-Avramoglu, and K. Adeli MEK-ERK Inhibition Corrects the Defect in VLDL Assembly in HepG2 Cells: Potential Role of ERK in VLDL-ApoB100 Particle Assembly Arterioscler. Thromb. Vasc. Biol., January 1, 2007; 27(1): 211 - 218. [Abstract] [Full Text] [PDF]

				S. Holder, M. Zemskova, C. Zhang, M. Tabrizizad, R. Bremer, J. W. Neidigh, and M. B. Lilly Characterization of a potent and selective small-molecule inhibitor of the PIM1 kinase Mol. Cancer Ther., January 1, 2007; 6(1): 163 - 172. [Abstract] [Full Text] [PDF]

				S. Zhuang, Y. Yan, R. A. Daubert, J. Han, and R. G. Schnellmann ERK promotes hydrogen peroxide-induced apoptosis through caspase-3 activation and inhibition of Akt in renal epithelial cells Am J Physiol Renal Physiol, January 1, 2007; 292(1): F440 - F447. [Abstract] [Full Text] [PDF]

				V. Adams, A. Linke, U. Wisloff, C. Doring, S. Erbs, N. Krankel, C. C. Witt, S. Labeit, U. Muller-Werdan, G. Schuler, et al. Myocardial expression of Murf-1 and MAFbx after induction of chronic heart failure: Effect on myocardial contractility Cardiovasc Res, January 1, 2007; 73(1): 120 - 129. [Abstract] [Full Text] [PDF]

				M. Rasar, D. B. DeFranco, and S. R. Hammes Paxillin Regulates Steroid-triggered Meiotic Resumption in Oocytes by Enhancing an All-or-None Positive Feedback Kinase Loop J. Biol. Chem., December 22, 2006; 281(51): 39455 - 39464. [Abstract] [Full Text] [PDF]

				H.-S. Je, F. Yang, J. Zhou, and B. Lu Neurotrophin 3 induces structural and functional modification of synapses through distinct molecular mechanisms J. Cell Biol., December 18, 2006; 175(6): 1029 - 1042. [Abstract] [Full Text] [PDF]

				S. Zhuang and R. G. Schnellmann A Death-Promoting Role for Extracellular Signal-Regulated Kinase J. Pharmacol. Exp. Ther., December 1, 2006; 319(3): 991 - 997. [Abstract] [Full Text] [PDF]

				V. Morales, I. Gonzalez-Robayna, M. P. Santana, I. Hernandez, and L. F. Fanjul Tumor Necrosis Factor-{alpha} Activates Transcription of Inducible Repressor Form of 3',5'-Cyclic Adenosine 5'-Monophosphate-Responsive Element Binding Modulator and Represses P450 Aromatase and Inhibin {alpha}-Subunit Expression in Rat Ovarian Granulosa Cells by a p44/42 Mitogen-Activated Protein Kinase-Dependent Mechanism Endocrinology, December 1, 2006; 147(12): 5932 - 5939. [Abstract] [Full Text] [PDF]

				N. R. Cunningham, S. C. Artim, C. M. Fornadel, M. C. Sellars, S. G. Edmonson, G. Scott, F. Albino, A. Mathur, and J. A. Punt Immature CD4+CD8+ Thymocytes and Mature T Cells Regulate Nur77 Distinctly in Response to TCR Stimulation J. Immunol., November 15, 2006; 177(10): 6660 - 6666. [Abstract] [Full Text] [PDF]

				M.-H. Kweon, V. M. Adhami, J.-S. Lee, and H. Mukhtar Constitutive Overexpression of Nrf2-dependent Heme Oxygenase-1 in A549 Cells Contributes to Resistance to Apoptosis Induced by Epigallocatechin 3-Gallate J. Biol. Chem., November 3, 2006; 281(44): 33761 - 33772. [Abstract] [Full Text] [PDF]

				Z. Lu, L. Serghides, S. N. Patel, N. Degousee, B. B. Rubin, G. Krishnegowda, D. C. Gowda, M. Karin, and K. C. Kain Disruption of JNK2 Decreases the Cytokine Response to Plasmodium falciparum Glycosylphosphatidylinositol In Vitro and Confers Protection in a Cerebral Malaria Model J. Immunol., November 1, 2006; 177(9): 6344 - 6352. [Abstract] [Full Text] [PDF]

				B. A. Watts III, T. George, and D. W. Good Aldosterone inhibits apical NHE3 and HCO3- absorption via a nongenomic ERK-dependent pathway in medullary thick ascending limb Am J Physiol Renal Physiol, November 1, 2006; 291(5): F1005 - F1013. [Abstract] [Full Text] [PDF]

				K. Zaniolo, M.-E. Gingras, M. Audette, and S. L. Guerin Expression of the Gene Encoding Poly(ADP-ribose) Polymerase-1 Is Modulated by Fibronectin during Corneal Wound Healing. Invest. Ophthalmol. Vis. Sci., October 1, 2006; 47(10): 4199 - 4210. [Abstract] [Full Text] [PDF]

				M. Kono, I. S. Dunn, P. J. Durda, D. Butera, L. B. Rose, T. J. Haggerty, E. M. Benson, and J. T. Kurnick Role of the Mitogen-Activated Protein Kinase Signaling Pathway in the Regulation of Human Melanocytic Antigen Expression Mol. Cancer Res., October 1, 2006; 4(10): 779 - 792. [Abstract] [Full Text] [PDF]

				W. Cao, L. Cheng, J. Behar, P. Biancani, and K. M. Harnett IL-1beta signaling in cat lower esophageal sphincter circular muscle Am J Physiol Gastrointest Liver Physiol, October 1, 2006; 291(4): G672 - G680. [Abstract] [Full Text] [PDF]

				E. Babilonia, D. Li, Z. Wang, P. Sun, D.-H. Lin, Y. Jin, and W.-H. Wang Mitogen-Activated Protein Kinases Inhibit the ROMK (Kir 1.1)-Like Small Conductance K Channels in the Cortical Collecting Duct J. Am. Soc. Nephrol., October 1, 2006; 17(10): 2687 - 2696. [Abstract] [Full Text] [PDF]

				Y.-H. Chen, M.-J. Lee, H.-H. Chang, P.-F. Hung, and Y.-H. Kao 17{beta}-Estradiol Stimulates Resistin Gene Expression in 3T3-L1 Adipocytes via the Estrogen Receptor, Extracellularly Regulated Kinase, and CCAAT/Enhancer Binding Protein-{alpha} Pathways Endocrinology, September 1, 2006; 147(9): 4496 - 4504. [Abstract] [Full Text] [PDF]

				E. Y. Tan, C. L. Richard, H. Zhang, D. W. Hoskin, and J. Blay Adenosine downregulates DPPIV on HT-29 colon cancer cells by stimulating protein tyrosine phosphatase(s) and reducing ERK1/2 activity via a novel pathway Am J Physiol Cell Physiol, September 1, 2006; 291(3): C433 - C444. [Abstract] [Full Text] [PDF]

				J. B. Patrone, S. E. Bish, and D. C. Stein TNF-{alpha}-Independent IL-8 Expression: Alterations in Bacterial Challenge Dose Cause Differential Human Monocytic Cytokine Response J. Immunol., July 15, 2006; 177(2): 1314 - 1322. [Abstract] [Full Text] [PDF]