Long-Distance Integration of Nuclear ERK Signaling Triggered by Activation of a Few Dendritic Spines

Zhai, Shenyu; Ark, Eugene D.; Parra-Bueno, Paula; Yasuda, Ryohei

doi:10.1126/science.1245622

Cited by 109 publications

(123 citation statements)

References 48 publications

(73 reference statements)

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“…Genetically encoded FRET reporters have emerged as useful tools for visualizing dynamic signaling processes in cells with high temporal and spatial resolution. In particular, the Erk activity sensor EKAR (28) and its newer-generation versions (29)(30)(31) have demonstrated robust Erk-activity reporting in a variety of mammalian cell contexts with sensitivity to distinct physiological stimuli (32)(33)(34). Given the close similarity of the enzyme/substrate interaction motifs between Erk1/2 and their MAPK homologs in yeast (SI Appendix, Fig.…”

Section: Resultsmentioning

confidence: 99%

Single-cell dynamics and variability of MAPK activity in a yeast differentiation pathway

Conlon

Gelin-Licht

Ganesan

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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In response to pheromones, yeast cells activate a MAPK pathway to direct processes important for mating, including gene induction, cellcycle arrest, and polarized cell growth. Although a variety of assays have been able to elucidate signaling activities at multiple steps in the pathway, measurements of MAPK activity during the pheromone response have remained elusive, and our understanding of single-cell signaling behavior is incomplete. Using a yeast-optimized FRET-based mammalian Erk-activity reporter to monitor Fus3 and Kss1 activity in live yeast cells, we demonstrate that overall mating MAPK activity exhibits distinct temporal dynamics, rapid reversibility, and a graded dose dependence around the K D of the receptor, where phenotypic transitions occur. The complex dose response was found to be largely a consequence of two feedbacks involving cyclin-mediated scaffold phosphorylation and Fus3 autoregulation. Distinct cell cycle-dependent response patterns comprised a large portion of the cell-to-cell variability at each dose, constituting the major source of extrinsic noise in coupling activity to downstream gene-expression responses. Additionally, we found diverse spatial MAPK activity patterns to emerge over time in cells undergoing default, gradient, and true mating responses. Furthermore, ramping up and rapid loss of activity were closely associated with zygote formation in mating-cell pairs, supporting a role for elevated MAPK activity in successful cell fusion and morphogenic reorganization. Altogether, these findings present a detailed view of spatiotemporal MAPK activity during the pheromone response, elucidating its role in mediating complex longterm developmental fates in a unicellular differentiation system. cell signaling | MAPK dynamics | Fus3 | mating pathway | yeast

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Section: Resultsmentioning

confidence: 99%

Single-cell dynamics and variability of MAPK activity in a yeast differentiation pathway

Conlon

Gelin-Licht

Ganesan

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Moreover, we observe that p90RSK phosphorylation occurred within the nucleus in a time-dependent manner, and at 120 min, it is dependent on afadin nuclear translocation. Interestingly, it has recently been shown that uncaging of glutamate on seven spines is sufficient to increase phospho-ERK1/2 levels in the nucleus of neurons, up to 120 min (20). Critically, p90RSK is directly phosphorylated by ERK1/2 (5); an intriguing possibility is that in the nucleus afadin could function as a scaffold to assemble transcription factors or histone-modifying proteins such as p90RSK, bringing these proteins together as a signaling complex, although future studies will need to test this hypothesis directly.…”

Section: Discussionmentioning

confidence: 99%

Coordinated Nuclear and Synaptic Shuttling of Afadin Promotes Spine Plasticity and Histone Modifications

VanLeeuwen

Rafalovich

Sellers

et al. 2014

Journal of Biological Chemistry

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Background: Coordinated synaptic and nuclear signaling is required for long lasting changes in neuronal morphology. Results: Afadin undergoes activity-dependent bi-directional shuttling to synapses and the nucleus resulting in dendritic spine remodeling and histone modifications. Conclusion: Afadin is required for coordinated signaling at synapses and the nucleus. Significance: Bi-directional trafficking of afadin is required for coordinated synaptic and nuclear signaling in response to activity-dependent stimulation.

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“…In contrast, more prolonged CREB activation (minutes to hours) in response to local LTP induction and restricted Ca 2ϩ influx in dendrites is thought to be mediated by local, postsynaptic CaMKII activation of the ERK pathway followed by slower, longer-distance translocation of ERK signaling from dendrites to nucleus to phosphorylate CREB (87,92,93). In addition, the CREB co-activator CRTC1 is dephosphorylated by CaN in response to LTCC Ca 2ϩ influx triggered by synaptic input to dendrites and then also slowly translocates distally to the nucleus where it is required for CREB-dependent gene expression underlying fear memory (83,94).…”

Section: Coordinated Kinase and Phosphatase Signaling In Postsynapticmentioning

confidence: 99%

Coordination of Protein Phosphorylation and Dephosphorylation in Synaptic Plasticity

Woolfrey

Dell’Acqua

2015

Journal of Biological Chemistry

113

105

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A central theme in nervous system function is equilibrium: synaptic strengths wax and wane, neuronal firing rates adjust up and down, and neural circuits balance excitation with inhibition. This push/pull regulatory theme carries through to the molecular level at excitatory synapses, where protein function is controlled through phosphorylation and dephosphorylation by kinases and phosphatases. However, these opposing enzymatic activities are only part of the equation as scaffolding interactions and assembly of multi-protein complexes are further required for efficient, localized synaptic signaling. This review will focus on coordination of postsynaptic serine/threonine kinase and phosphatase signaling by scaffold proteins during synaptic plasticity. Control of Synaptic Strength through Balanced Phosphorylation/DephosphorylationA defining aspect of the mammalian brain is its profound capacity for experience-dependent plasticity that modifies the strength of specific synaptic connections between neurons. Two well studied opposing forms of synaptic plasticity at excitatory synapses are long-term potentiation (LTP) 2 and longterm depression (LTD), which strengthen and weaken synapses, respectively. LTP and LTD have been most heavily studied in a brain region called the hippocampus where they support spatial and declarative learning and memory. LTP and LTD are induced by Ca 2ϩ influx through postsynaptic NMDAtype ionotropic glutamate receptors (NMDARs) and are expressed by long-lasting increases or decreases, respectively, in the function of AMPA-type ionotropic glutamate receptors (AMPARs) that mediate the bulk of excitatory synaptic transmission (1, 2). NMDARs are heterotetrameric assemblies most commonly containing two GluN1 and two GluN2A-2D subunits and are permeable to Na ϩ , K ϩ , and Ca 2ϩ . At hippocampal synapses, NMDARs are assembled from GluN1, GluN2A, and GluN2B subunits. AMPARs are heterotetrameric assemblies of GluA1-GluA4 subunits, with most being permeable only to Na ϩ and K ϩ due to inclusion of GluA2 subunits that prevent Ca 2ϩ influx (3). However, hippocampal neurons can also express small numbers of Ca 2ϩ -permeable AMPARs lacking GluA2 subunits (i.e. GluA1 homomers) that primarily reside in extrasynaptic and intracellular locations but can be recruited to synapses during plasticity and following neuronal injuries (4). Intriguingly, there is much commonality in the molecular mechanisms underlying the ostensibly antagonistic processes of LTP and LTD; both require correlated pre-and postsynaptic activity leading to NMDAR Ca 2ϩ influx and are mediated by overlapping sets of enzymes. However, it is the ability of the synapse to detect subtle differences in Ca 2ϩ and other second messengers and efficiently transduce these signals to discrete downstream signaling pathways that permits diametrically opposed outcomes to arise from grossly similar synaptic stimuli.Ultimately, excitatory synaptic plasticity must add, remove, or modify AMPARs to alter synaptic strength. Although AMPAR regulation during plas...

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Long-Distance Integration of Nuclear ERK Signaling Triggered by Activation of a Few Dendritic Spines

Cited by 109 publications

References 48 publications

Single-cell dynamics and variability of MAPK activity in a yeast differentiation pathway

Single-cell dynamics and variability of MAPK activity in a yeast differentiation pathway

Coordinated Nuclear and Synaptic Shuttling of Afadin Promotes Spine Plasticity and Histone Modifications

Coordination of Protein Phosphorylation and Dephosphorylation in Synaptic Plasticity

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