Mitogen-Activated Protein Kinase Signaling in Cerebrovascular Disease

Mitogen-Activated Protein Kinase Signaling

Cells respond to their extracellular environment via common intracellular signaling systems. Mitogen-activated protein kinases (MAPKs) are serine–threonine kinases that mediate intracellular signaling involved in regulating protein and cell functioning related to membrane, intra- and intercellular processes and transformation, proliferation/growth, differentiation, survival, and death. The mammalian MAPK family consists of an extracellular signal–regulated kinase (ERK) signaling arm and the stress-activated protein kinases (SAPK) consisting of a p38 arm and c-Jun NH2-terminal kinase (JNK) arm, with ERK, p38, and JNK each existing in several isoforms. As shown in Fig. 53.1 , the cascade of MAPK signaling consists of a MAPK kinase kinase (MAP3K), a MAPK kinase (MAP2K), and a MAPK (left side). MAP3Ks phosphorylate and activate MAP2Ks, which in turn phosphorylate and activate MAPKs. The phosphorylated MAPK then interacts with cellular substrates and/or translocates to the nucleus to modulate diverse biological responses. Thus, the activated MAPKs ERK, p38, and JNK (right side) phosphorylate various target/substrate proteins including transcription factors (e.g., Elk-1, ATF2, and c-Jun, respectively) that modify cellular function and phenotype. Growth factor stimulation of the ERK pathway modulates the activity of many cellular proteins and transcriptional factors modifying cell functioning, proliferation, differentiation, migration, and survival. The SAPK p38 and JNK pathways are weakly activated by growth factors, but are strongly activated by stress stimuli such as ischemia and/or hemorrhage, oxygen free radicals, and inflammatory cytokines such as interleukin-1 beta (IL-1β) and tumor necrosis factor alpha (TNFα) resulting in altered transcription, translation, and activation of factors involved in cell proliferation, differentiation, inflammatory cytokines and inflammation, and cellular apoptosis/death.

Although initially identified as independent arms of intracellular signaling pathways activated in response to distinct extracellular stimuli, it is now understood that there is significant cross talk/interaction between these three MAPK signaling arms. This suggests that these pathways can also be considered as components of much larger signaling networks that still needs to be understood. As examples, both ERK and p38 pathways activate common transcription factors such as Elk-1, Sap-1a, and cyclic-AMP response element–binding protein (CREB). Some stimuli activate CREB through p38 and ERK, whereas others can activate ERK through activation of the p38 pathway. In addition, ERK and p38 pathways share common intracellular kinase substrates and can mediate growth factor and stress-induced activation of CREB. It is clear that these signaling systems are far from being fully understood and new data continue to emphasize the interactions or cross talk between MAPK signaling in cellular changes. Alternative signaling pathways will emerge as our knowledge of kinase biology increases via the evaluation of transgenic animals and the development of new, selective kinase inhibitors. Thus, modulation of a single kinase may alter signaling through cross talk or via alternative/to be discovered pathway interactions. All these can depend on signal strength, duration, and location, and the precise control of kinase activation, including the detailed temporal activations in development or in disease pathology, and the specific scaffolding proteins that tether MAPK signaling components into discrete signaling cascades. Thus, the complexity of kinase signaling changes and their complex interactions must be considered with outcome changes in animal models of cerebrovascular disease using selective small-molecule inhibitors as is discussed in the following sections. The reference list provided , although a very short list, does provide the primary connection to the highly summarized information contained in this chapter.

Ischemic Stroke

Ischemic stroke results in significant brain injury and disability. Cerebral ischemia produces many pathological changes that results in impaired cellular regulation, intercommunication and cell loss/brain infarction. Following ischemia many factors are released, including growth factors, cytokines, glutamate, and oxygen free radicals that can stimulate the activation of MAPK pathways. The consequence of kinase activation is dependent on changes in intracellular and extracellular environment (i.e., influences from other cell changes), the cell type, the number of kinase pathways activated at any given time, and the duration of kinase activation. The complex balance between ischemic cell survival and death-mediated changes in cerebral ischemia has been emphasized by many researchers. Kinase activation after ischemia can be related to other cell changes or be central to cell death. Future optimum therapeutic intervention to improve outcome might require selective or a specific profile of kinase inhibitors as addressed in the following section.