MAP kinases are key regulatory components acting on many cellular processes such as embryogenesis, differentiation, proliferation, cell death, and acute hormonal responses. MAP kinases are activated by a protein kinase cascade, consisting of a MAP/ERK kinase kinase (MEKK), which activates a MEK which activates a MAP kinase. ERK1 and ERK2, the first mammalian MAP kinases identified, serve as prototypes for the behavior of the many related enzymes. The functions of these MAP kinases depend on their activation, their subcellular localizations, their protein-protein interactions, and their substrate specificities. We propose to continue to investigate mechanisms controlling MAP kinase pathways as follows. The nuclear uptake of ERK2 is essential for some of its most important functions. We will define mechanisms of subcellular localization of ERKI/2 by examining import and export by reconstitution in permeabilized cells, and microinjection and transfection in intact cells. We will define mechanisms determining functional complexes of MAP kinases. To do this we will use a cDNA library of mutant ERK2 molecules from which we will isolate ERK2 mutants that lack high affinity interactions with proteins including substrates, activators, and phosphatases. We will study the functions of the loss-of-function ERK2 mutants to determine the roles of individual interactions in inducing ERK2-dependent phenotypes. The ERK2 activator MEK1 binds to molecules other than ERK1/2 and Raf that are essential for signal transmission through the cascade. We will attempt to identify proteins that bind MEK1 through its proline-rich insert and determine their mechanisms of action. We will study ERK5, another member of the MAP kinase family. ERK5 is most similar to ERK2, and cooperates with ERK2 to transform cells. We will examine the mechanisms of ERK5 regulation, and determine how its actions relate to the functions of ERK1/2. We will also study a putative ERK5 ortholog in C. elegans to use genetic studies to complement work in mammals.
| Thorne, Curtis A; Chen, Ina W; Sanman, Laura E et al. (2018) Enteroid Monolayers Reveal an Autonomous WNT and BMP Circuit Controlling Intestinal Epithelial Growth and Organization. Dev Cell 44:624-633.e4 |
| Guerra, Marcy L; Kalwat, Michael A; McGlynn, Kathleen et al. (2017) Sucralose activates an ERK1/2-ribosomal protein S6 signaling axis. FEBS Open Bio 7:174-186 |
| Kalwat, Michael A; Cobb, Melanie H (2017) Mechanisms of the amplifying pathway of insulin secretion in the ? cell. Pharmacol Ther 179:17-30 |
| Dyachok, Julia; Earnest, Svetlana; Iturraran, Erica N et al. (2016) Amino Acids Regulate mTORC1 by an Obligate Two-step Mechanism. J Biol Chem 291:22414-22426 |
| McReynolds, Andrea C; Karra, Aroon S; Li, Yan et al. (2016) Phosphorylation or Mutation of the ERK2 Activation Loop Alters Oligonucleotide Binding. Biochemistry 55:1909-17 |
| Lidke, Diane S; Huang, Fang; Post, Janine N et al. (2010) ERK nuclear translocation is dimerization-independent but controlled by the rate of phosphorylation. J Biol Chem 285:3092-102 |
| Jivan, Arif; Ranganathan, Aarati; Cobb, Melanie H (2010) Reconstitution of the nuclear transport of the MAP kinase ERK2. Methods Mol Biol 661:273-85 |
| Duan, Lingling; Cobb, Melanie H (2010) Calcineurin increases glucose activation of ERK1/2 by reversing negative feedback. Proc Natl Acad Sci U S A 107:22314-9 |
| Lawrence, Michael C; Shao, Chunli; McGlynn, Kathleen et al. (2009) Multiple chromatin-bound protein kinases assemble factors that regulate insulin gene transcription. Proc Natl Acad Sci U S A 106:22181-6 |
| Lawrence, Michael C; McGlynn, Kathleen; Shao, Chunli et al. (2008) Chromatin-bound mitogen-activated protein kinases transmit dynamic signals in transcription complexes in beta-cells. Proc Natl Acad Sci U S A 105:13315-20 |
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