Chapter Four - Spatiotemporal Modulation of ERK Activation by GPCRs
Introduction
Extracellular-signal regulated kinase (ERK) is the final effector protein of a typical mitogen-activated protein (MAP) kinase phosphorelay cascade and is the key molecule that regulates cellular responses mediated through receptor tyrosine kinases (RTKs) (chapter “ERK activation pathways downstream of GPCRs” by Jain et al.). The activation of ERK happens through both canonical and noncanonical modes. The canonical (or typical) ERK protein activation occurs through the process of binding of different growth factors to their respective receptors, which are single-pass membrane-anchored RTKs. The ligand binding to the receptor initiates a MAP kinase cascade involving sequential activation of adapter proteins and kinases, viz., Grb2 → Sos → Ras → Raf → MEK, and ultimately leading to ERK phosphorylation. On the other hand, a noncanonical activation of ERK by GPCRs can occur through several different mechanisms, which can utilize many distinct as well as few common signaling molecules (discussed in chapter “ERK activation pathways downstream of GPCRs” by Jain et al.). Such a design evokes multiple questions, such as why cross talk should be there; why share regulators over efficiently insulated cascades; and importantly, how is the specificity in the signaling outcomes achieved.
The component sharing may be an evolutionary process wherein by utilizing the same set of regulators, the fidelity of downstream reactions is ensured and the same sets of regulatory checkpoints essential for minimizing spurious activations are invoked. Despite this, convergence of multiple signaling pathways to one protein which can generate multiple distinct outputs warrants understanding of the decision-making design for the single terminal ERK protein. In this simplistic design, the obvious question is as to what process or mechanisms the cell uses to regulate the ERK protein in the backdrop of an extensive, interrelated and cross-regulated network and still confer specificity to the signaling responses as well as manifest different cellular fates. One way to examine this is by mapping the individual signaling pathways onto a network analogous to a route map. Here each decision-making step is akin to an intersection, where a cell decides to proceed on a selected route; which could be to die, to differentiate, to proliferate, or to survive, which are some of the common cell fates regulated by the ERK protein. In this design, spatial and temporal navigation is used at a considerably high amount to avoid misdirection and accidents. On a similar design, the cellular signaling network also regulates the behavior of participating proteins at both spatial and temporal scales to ensure that it generates the most appropriate output.
In the context of ERK, we present the current understanding about its spatiotemporal regulation; what factors or regulators modulate these mechanisms and how these changes are interpreted by the ERK protein to bring about different and sometimes completely opposite cellular responses such as proliferation vs differentiation. We also highlight the spatial and temporal regulators involved in both canonical (RTK) and noncanonical (GPCRs) pathways.
Section snippets
Spatiotemporal Regulators in Canonical Activation Cascade of ERK
Spatiotemporal modulation is fundamental to every signaling cascade and this is primarily because of the need of transmitting a stimulus from outside to the inside of the cell, which needs to adapt to the cue. The information flow from exterior to interior essentially demands flow of information across a spatial domain, which also necessitates involvement of a temporal dimension, as the flow occurs over a time duration. Several molecules and processes have been shown to regulate the ERK
Spatiotemporal Regulators Involved in Noncanonical or GPCR-Mediated Cross-Activation of ERK
The modulation of ERK activity, as mentioned earlier, is governed through spatial and temporal regulation of the upstream signaling complexes, which includes G-protein-coupled receptors (GPCRs) as noncanonical activators. Although the specificity of ERK activation-dependent responses is regulated by multiple mechanisms including the scaffolding of the signaling complexes (as described earlier), the diversity of the outcomes outnumbers the possible scaffolds owing to cross talk. As discussed in
GPCR-Mediated Activation of MAPK Cascades: Evidence of Spatiotemporal Modulation in Other Organisms
GPCR signaling-mediated MAPK activation has been widely documented using mammalian cells as models. However, various reports have demonstrated the presence of the transactivation processes in non-mammalian systems as well. One of the most well-documented systems is that of yeast, wherein GPCR-stimulated activation of yeast-mating pathways, which are essentially MAPK pathways, has been observed.
The yeast pheromone response pathway processes extracellular pheromones to modulate transcription and
Concluding Remarks
Overall, it is now well established that activation of MAP kinase molecules which is typically recorded through monitoring changes in the phosphorylation status of the participating molecules and most often for the terminal kinase ERK, tell only the partial story. The ultimate outcome as well as the quantum and localization of the activated ERK is dictated by the spatiotemporal dynamics of all the members of the MAPK signaling cascade. The spatial component brings about the activation of
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Retention of ERK in the cytoplasm mediates the pluripotency of embryonic stem cells
2023, Stem Cell ReportsCitation Excerpt :To regulate these distinct functions, ERK1/2 are well regulated by phosphorylation, scaffolding, and subcellular localization (Kholodenko et al., 2010; Shaul and Seger, 2007). The subcellular localization of ERK1/2 is dynamic, as they are found in the cytoplasm of resting cells, but change their localization upon stimulation, reaching mainly the nucleus, but also the mitochondria, endosomes, cytoskeleton, and others (Watson et al., 2018; Wortzel and Seger, 2011). These changes in localization are important for proper cellular functioning upon stimulation and assist in the determination of cell fate.
The MAP kinase ERK5/MAPK7 is a downstream effector of oxytocin signaling in myometrial cells
2022, Cellular SignallingCitation Excerpt :The mechanism linking ERK5 activation to COX-2 induction in our model remains to be uncovered but the presence of a MEF2 responsive element on the COX-2 promoter [42] allows us to speculate that ERK5 increases the activity of MEF2 transcription factors on their cognate response elements regulating gene expression [39,41]. Multiple mechanisms have been proposed to explain how GPCRs activate ERK1/2 [43], while ERK5 activation mechanisms remain poorly documented [20,21]. To address this question, we used a pharmacological approach targeting the Gq and Gi pathways downstream of OTR in the myometrium [33].
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2021, Cellular SignallingCitation Excerpt :At the age of 21 days, DUSP5 knockout mice had more cardiomyocytes, suggesting that DUSP5 expression at the cardiac base limits cardiomyocyte proliferation in the early post-natal period. The information passes through the ERK1/2 signaling cascade is encoded spatiotemporally in the duration, amplitude, stability, frequency, and subcellular localization of the signal [32]. Although many studies concentrated on the effects of different DUSPs on the amplitude of the signal, DUSPs can potentially affect the other components such as the frequency or the spatial localization of the signal.
The ER-mitochondria Ca<sup>2 +</sup> signaling in cancer progression: Fueling the monster
2021, International Review of Cell and Molecular BiologyCitation Excerpt :Other organelles such as the mitochondria, the lysosomes and the Golgi complex also accumulate Ca2 +, but to a lesser extent when compared with the SR/ER (Prins and Michalak, 2011). Upon several types of stimulus, such as membrane depolarization or ligand engaged G protein-coupled receptors (Watson et al., 2018) cytosolic Ca2 + concentration can rapidly increase from 100 nM to 1 μM or more (Bagur and Hajnóczky, 2017; Bootman and Bultynck, 2020), driven either by intracellular stores, extracellular flux or both. Ca2 + from the extracellular space enters the cytoplasm through a wide variety of Ca2 +-permeable channels located in the plasma membrane including; voltage-gated Ca2 + channels (VGCCs) (Nanou and Catterall, 2018), the Ca2 + permeable members of the transient receptor potential channels (TRPs) (Pedersen et al., 2005), store operated Ca2 + channels (SOC) (Prakriya and Lewis, 2015), ATP-activated P2X channels (Burnashev, 1998; North, 2002; Pankratov and Lalo, 2014) and stretch-activated Ca2 + channels, as PIEZO (De Felice and Alaimo, 2020).
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Equal contribution.
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Present address: University of Texas Southwestern Medical Centre, Dallas, TX, United States.