[Frontiers in Bioscience 8, d369-391, January 1, 2003]
MITOGEN-ACTIVATED PROTEIN KINASE PATHWAYS IN REDOX SIGNALING
Childrens Hospital Los Angeles Research Institute, Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, CA 90027, USA
FIGURES
Figure 1. Three-tiered MAPK Cascades. Each MAP cascade is composed of three kinases that are sequentially activated. The change in shape is a graphical depiction for the activated form of the kinases but does not necessarily imply changes in protein conformation.
Figure 2. The ERK Cascade. The ERK cascade can be activated through activation of the small GTPases, Ras and Rap1 by various guanine nucleotide exchange factors. The activation of Raf-1 requires formation of a complex with activated Ras at the plasma membrane where further activation events, including phosphorylation, take place. The 14-3-3 proteins play an essential role in maintaining Raf-1 in an inactive conformation in resting cells and may also play a role in facilitating Raf-1 translocation and complex formation with Ras at the plasma membrane. KSR has gained credit as a scaffold protein for the ERK cascade.
Figure 3. The SAPK Cascades. (A) The SAPK modules are not entirely identified at the level of the MAPKKK, as many kinases have been shown to activate the SAPK. (B) Depicted are some of the scaffold proteins that have been characterized for the JNK modules. See text for details.
Figure 4. MAPK and Transcription factors as Substrates. (A) Each MAPK phosphorylates specific (black) but also overlapping (grey??) substrates. They also phosphorylate kinases with transcription factors as substrates, such as RSK and MAPKAPK family of proteins. Overall, the MAPK can affect SRE, CREB, MEF and AP-1 response elements that are present either alone or in tandem in the promoter of many genes such as c-fos and c-jun (B), making the MAPK essential regulators of transcription.
Figure 5. Mechanism of reversible protein thiol modification by ROS. PTP contain a critical cysteine in their catalytic site, which is in the form of a thiolate. Oxidation by H2O2 results in formation of a sulfenic acid intermediate that inhibits the enzymatic activity (L ), which is then restored (J ) through the action of thiols.
Figure 6. Proposed mechanisms for ROS-mediated activation of the MAPK. ROS are produced in the cells in a controlled fashion through the enzymatic activity of NADPH oxidase of the Nox family and possibly by the mitochondria, although the exact mechanism is unclear for the latter. Ras, Src-like kinases, PTP and thioredoxin can interact with ROS through specific cysteine residues, resulting in alteration of their activity. While the reversible oxidation of PTP by ROS is well characterized in vitro and in vivo, their targets in the various MAPK pathways have not been identified yet. See text for details.