Primary Cilium Formation and Ciliary Protein Trafficking Is Regulated by the Atypical MAP Kinase MAPK15 in<i>Caenorhabditis elegans</i>and Human Cells

Kazatskaya, Anna; Kuhns, Stefanie; Lambacher, Nils J.; Kennedy, Julie; Brear, Andrea G.; McManus, Gavin; Sengupta, Piali; Blacque, Oliver E.

doi:10.1534/genetics.117.300383

Cited by 26 publications

(41 citation statements)

References 91 publications

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“…These data provide new insight into the functions of the IMC apical cap in regulating parasite development. Using proximity biotinylation, we defined the AC9 interaction network, which includes ERK7, a conserved MAPK that regulates ciliogenesis in metazoa (15,16), and which we have recently shown is required for conoid formation (17). We demonstrate that AC9 is required for the correct localization of ERK7 at the apical cap, and that this scaffolding interaction is essential for apical complex maturation.…”

Section: Introductionmentioning

confidence: 90%

“…AC9 and ERK7 colocalize at the apical cap ( Figure 3A) and proximity ligation immunofluorescence (34) demonstrated that they are closely associated at this site ( Figure 3B). ERK7 is a member of an early-branching MAPK family that is conserved throughout eukaryotes (35,36) and has been implicated as a facilitator of ciliogenesis in metazoa (15,16) and…”

Section: Proximity Biotinylation Reveals Ac9 Interacts With the Map Kmentioning

confidence: 99%

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Ancient MAPK ERK7 is regulated by an unusual inhibitory scaffold required for Toxoplasma apical complex biogenesis

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O’Shaughnessy

Moon

et al. 2020

Preprint

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Apicomplexan parasites use a specialized cilium structure called the apical complex to organize their secretory organelles and invasion machinery. The apical complex is integrally associated with both the parasite plasma membrane and an intermediate filament cytoskeleton called the inner membrane complex (IMC). While the apical complex is essential to the parasitic lifestyle, little is known about the regulation of apical complex biogenesis. Here, we identify AC9 (apical cap protein 9), a largely intrinsically disordered component of the Toxoplasma gondii IMC, as essential for apical complex development, and therefore for host cell invasion and egress. Parasites lacking AC9 fail to successfully assemble the tubulin-rich core of their apical complex, called the conoid. We use proximity biotinylation to identify the AC9 interaction network, which includes the kinase ERK7. Like AC9, ERK7 is required for apical complex biogenesis. We demonstrate that AC9 directly binds ERK7 through a conserved C-terminal motif and that this interaction is essential for ERK7 localization and function at the apical cap. The crystal structure of the ERK7:AC9 complex reveals that AC9 is not only a scaffold, but also inhibits ERK7 through an unusual set of contacts that displaces nucleotide from the kinase active site. ERK7 is an ancient and auto-activating member of the mitogen-activated kinase family and we have identified its first regulator in any organism. We propose that AC9 dually regulates ERK7 by scaffolding and concentrating it at its site of action while maintaining it in an "off" state until the specific binding of a true substrate. Significance StatementApicomplexan parasites include the organisms that cause widespread and devastating human diseases such as malaria, cryptosporidiosis, and toxoplasmosis. These parasites are named for a structure, called the "apical complex," that organizes their invasion and secretory machinery. We found that two proteins, apical cap protein 9 (AC9) and an enzyme called ERK7 work together to facilitate apical complex assembly. Intriguingly, ERK7 is an ancient molecule that is found throughout Eukaryota, though its regulation and function are poorly understood. AC9 is a scaffold that 2 concentrates ERK7 at the base of the developing apical complex. In addition, AC9 binding likely confers substrate selectivity upon ERK7. This simple competitive regulatory model may be a powerful but largely overlooked mechanism throughout biology.

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Section: Introductionmentioning

confidence: 90%

Section: Proximity Biotinylation Reveals Ac9 Interacts With the Map Kmentioning

confidence: 99%

Ancient MAPK ERK7 is regulated by an unusual inhibitory scaffold required for Toxoplasma apical complex biogenesis

Back

O’Shaughnessy

Moon

et al. 2020

Preprint

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“…Together, these data indicate that disruption of C05D10.2 causes URX overgrowth. [39][40][41]. As URX is neither ciliated nor dopaminergic, it is unclear how these roles relate to URX overgrowth.…”

Section: Urx Dendrite Overgrowth Mutants Are Alleles Of Mapk-15 and Smentioning

confidence: 99%

“…To determine where mapk-15 is expressed, we generated a transcriptional reporter and found that it labels URX as well as many other head sensory neurons at all larval stages ( Fig. 4A; expression in ciliated sensory neurons is also reported in [39][40][41]), suggesting mapk-15 could act cell-autonomously in URX.…”

Section: Mapk-15 Acts Cell-autonomously To Constrain Dendrite Growthmentioning

confidence: 99%

“…Second, its interaction with autophagic components is mediated through its conserved LC3interacting region [49], which we found to be required to restrict dendrite growth. Third, in C. elegans ciliated neurons, MAPK-15 localizes near the periciliary membrane compartment, a region that is enriched for proteins involved in membrane trafficking [40,41]. Fourth, the role of MAPK-15 in C. elegans dopaminergic neurons has been suggested to involve membrane trafficking of a dopamine transporter at synapses [39].…”

Section: Mapk-15 and The Control Of Sensory Dendrite Lengthmentioning

confidence: 99%

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A neuronal MAP kinase constrains growth of aC. eleganssensory dendrite throughout the life of the organism

McLachlan

Beets

Bono

et al. 2018

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Neurons develop elaborate morphologies that provide a model for understanding cellular architecture. By studying C. elegans sensory dendrites, we previously identified genes that act to promote the extension of ciliated sensory dendrites during embryogenesis. Interestingly, the nonciliated dendrite of the oxygensensing neuron URX is not affected by these genes, suggesting it develops through a distinct mechanism.Here, we use a visual forward genetic screen to identify mutants that affect URX dendrite morphogenesis.We find that disruption of the MAP kinase MAPK-15 or the β H -spectrin SMA-1 causes a phenotype opposite to what we had seen before: dendrites extend normally during embryogenesis but begin to overgrow as the animals reach adulthood, ultimately extending up to 150% of their normal length. SMA-1 is broadly expressed and acts non-cell-autonomously, while MAPK-15 is expressed in many sensory neurons including URX and acts cell-autonomously. MAPK-15 acts at the time of overgrowth, localizes at the dendrite ending, and requires its kinase activity, suggesting it acts locally in time and space to constrain dendrite growth. Finally, we find that the oxygen-sensing guanylate cyclase GCY-35, which normally localizes at the dendrite ending, is localized throughout the overgrown region, and that overgrowth can be suppressed by overexpressing GCY-35 or by genetically mimicking elevated cGMP signaling. These results suggest that overgrowth may correspond to expansion of a sensory compartment at the dendrite ending, reminiscent of the remodeling of sensory cilia or dendritic spines. Thus, in contrast to established pathways that promote dendrite growth during early development, our results reveal a distinct mechanism that constrains dendrite growth throughout the life of the animal, possibly by controlling the size of a sensory compartment at the dendrite ending.

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Cellular and physiological roles of the conserved atypical MAP kinase ERK7

2022

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Extracellular signal‐regulated kinase 7 (ERK7), also known as ERK8 and MAPK15, is an atypical member of the MAP kinase family. Compared with other MAP kinases, the biological roles of ERK7 remain poorly understood. Recent work, however, has revealed several novel functions for ERK7. These include a highly conserved essential role in ciliogenesis, the ability to control cell growth, metabolism and autophagy, as well as the maintenance of genomic integrity. ERK7 functions through phosphorylation‐dependent and ‐independent mechanisms and it is activated by cellular stressors, including DNA‐damaging agents, and nutrient deprivation. Here, we summarize recent developments in understanding ERK7 function, emphasizing its conserved roles in cellular and physiological regulation.

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Primary Cilium Formation and Ciliary Protein Trafficking Is Regulated by the Atypical MAP Kinase MAPK15 inCaenorhabditis elegansand Human Cells

Cited by 26 publications

References 91 publications

Ancient MAPK ERK7 is regulated by an unusual inhibitory scaffold required for Toxoplasma apical complex biogenesis

Ancient MAPK ERK7 is regulated by an unusual inhibitory scaffold required for Toxoplasma apical complex biogenesis

A neuronal MAP kinase constrains growth of aC. eleganssensory dendrite throughout the life of the organism

Cellular and physiological roles of the conserved atypical MAP kinase ERK7

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