Protein-protein interactions in the regulation of the extracellular signal-regulated kinase.
ABSTRACT The extracellular signal-regulated kinase (ERK) cascade is a central intracellular signaling pathway that is activated by a variety of extracellular stimuli, and thereby regulates cellular processes such as proliferation, differentiation, and oncogenic transformation. To execute these functions, the signals of those stimuli are transmitted to the cytosolic and nuclear targets in a rapid and specific manner. In the last few years it has become clear that the specificity and the rapid function of the ERK cascade is largely determined by protein-protein interactions with various signaling components and substrates. This review describes interactions of ERK with its immediate regulators, scaffold proteins, substrates, and localizing proteins, and shows their involvement in the functioning of the ERK cascade. Understanding the full scope of ERK-interactions is important for the development of new drugs for the treatment of cancer and other diseases.
Article: Gatekeepers of the nucleus.[show abstract] [hide abstract]
ABSTRACT: Nuclear pore complexes (NPCs) form the site for entry and exit from the nucleus. A convergence of studies have defined the physical framework for the nuclear transport mechanism. This includes definition of the soluble transport machinery required for protein and RNA movement, x-ray structure analysis of transport factors, definitive compositional analysis of yeast NPCs, and documentation of the relative steady state arrangement of NPC components within the portal. With this information, researchers are now in the exciting position to examine the dynamic interplay between shuttling transport factors and the static pore complex.Science 06/2000; 288(5470):1374-7. · 31.03 Impact Factor
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ABSTRACT: An evolutionarily conserved mitogen-activated protein kinase pathway--the high osmolarity glycerol (HOG) pathway--mediates the hyperosmotic response in Saccharomyces cerevisiae. A variety of powerful approaches has generated a comprehensive picture of how cells respond to this stress condition. Several presumptive osmosensors on the cell surface recruit and activate downstream signaling components, which regulate the activity of transcription factors to control gene expression.Trends in Genetics 09/2002; 18(8):405-12. · 9.77 Impact Factor
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ABSTRACT: The classical mitogen-activated protein kinase (MAPK, also known as ERK) pathway is widely involved in eukaryotic signal transductions. In response to extracellular stimuli, MAPK becomes activated and translocates from the cytoplasm to the nucleus. At least two pathways for the nuclear import of MAPK are shown to exist; passive diffusion of a monomer and Ran-dependent active transport of a dimer, the detailed molecular mechanism of which is unknown. In this study, we have reconstituted nuclear import of MAPK in vitro by using digitonin-permeabilized cells with GFP-fused MAPK protein (GFP-MAPK), which is too large to pass through the nuclear pore by passive diffusion. GFP-MAPK was able to accumulate in the nucleus irrespective of its phosphorylation state. This import of GFP-MAPK occurred even in the absence of any soluble cytosolic factors or ATP but was inhibited by wheat germ agglutinin or an excess amount of importin-beta or at low temperatures. Moreover, MAPK directly bound to an FG repeat region of nucleoporin CAN/Nup214 in vitro. Taken together, these results suggest the third pathway for nuclear import of MAPK, in which MAPK passes through the nuclear pore by directly interacting with the nuclear pore complex.Journal of Biological Chemistry 12/2001; 276(45):41755-60. · 4.65 Impact Factor