The road to ERK activation: Do neurons take alternate routes?

Abstract

The ERK cascade is a central signaling pathway that regulates a wide variety of cellular processes including proliferation, differentiation, learning and memory, development, and synaptic plasticity. A wide range of inputs travel from the membrane through different signaling pathway routes to reach activation of one set of output kinases, ERK1&2. The classical ERK activation pathway beings with growth factor activation of receptor tyrosine kinases. Numerous G-protein coupled receptors and ionotropic receptors also lead to ERK through increases in the second messengers calcium and cAMP. Though both types of pathways are present in diverse cell types, a key difference is that most stimuli to neurons, e.g. synaptic inputs, are transient, on the order of milliseconds to seconds, whereas many stimuli acting on non-neural tissue, e.g. growth factors, are longer duration. The ability to consolidate these inputs to regulate the activation of ERK in response to diverse signals raises the question of which factors influence the difference in ERK activation pathways. This review presents both experimental studies and computational models aimed at understanding the control of ERK activation and whether there are fundamental differences between neurons and other cells. Our main conclusion is that differences between cell types are quite subtle, often related to differences in expression pattern and quantity of some molecules such as Raf isoforms. In addition, the spatial location of ERK is critical, with regulation by scaffolding proteins producing differences due to colocalization of upstream molecules that may differ between neurons and other cells.

Figure 1:. Schematic representation of the classical ERK cascade.

Activation of receptor upon ligand binding results in recruitment of the Guanosine Exchange Factor (GEF) that turns on the Ras family protein (exchange of GDP for GTP). Ras family proteins are turned off by GTPase Activating Proteins (GAP) that accelerate hydrolysis of GTP to GDP. Binding of RasGTP/RapGTP to Raf activates it and initiates the sequential phosphorylation steps of MEK which in turn activates ERK, which can phosphorylate either cytosolic or nuclear substrates.

Figure 2:. Scaffolding proteins in ERK signaling pathways:

In the cytosol, upon stimulation KSR translocates to the membrane and scaffolds a pool of Raf/MEK/ERK that is activated by PKC. GPCRs activate ERK through either G-proteins (not shown) or β-arrestin with different temporal dynamics. IQGAP1 scaffolds Raf/MEK/ERK in dendritic spines, and binding of calmodulin causes dissociation from actin. ppERK can either dimerize in the cytoplasm or translocate to the nucleus, though ERK scaffolded by β-arrestin does not translocate to the nucleus.

Figure 3:. Numerous signaling pathways contribute to ERK activation in CA1 pyramidal neurons:

GPCRs stimulate the intracellular production of cAMP and calcium in both dendrites and dendritic spines. cAMP contributes to ERK through activation of PKA and RapGEFs (e.g. Epac). Calcium in both dendrites and dendritic spines leads to ERK by activating molecules such as PKC (which enhances C-Raf activity by phosphorylation) and RasGEFs (e g. RasGRF). Calcium activation of CaMKII modulates SynGap activity in dendritic spines. RTKs, such as TrkA, TrkB and EGFR, activate Ras family proteins through intermediate molecules. Note that all molecules, except for SynGap, are found in both dendrites and dendritic spines. Most of these molecules also are found in principal neurons of striatum, cerebellum and neocortex.

Figure 4:. Schematic diagram of GPCR activation of ERK as well as feedback mechanisms.

GPCRs influence cAMP and calcium through three major groups of heterotrimeric GTP binding proteins: Gs, Gi and Gq. Some feedback mechanisms are confined within ERK pathways, whereas others involve kinases activated by GPCRs.