A STRIPAK complex mediates axonal transport of autophagosomes and dense core vesicles through PP2A regulation

Neisch, Amanda L.; Neufeld, Thomas P.; Hays, Thomas S.

doi:10.1083/jcb.201606082

Cited by 88 publications

(88 citation statements)

References 94 publications

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“…In this role, PP2A in the STRIPAK deactivates Hippo kinases, which in turn leads to decreased Warts/LATS kinase activation. Notably, fly Mob4 and the STRIPAK complex are required for normal formation of synaptic boutons at fly neuromuscular junctions, a process regulated by Tricornered and Mob2 (Schulte et al, 2010;Neisch et al, 2017).…”

Section: The Stripak Complex Is a Negative Regulator Of Hippo Signalingmentioning

confidence: 99%

“…The roles of other STRIPAK components are less understood. An intact STRIPAK complex is required for negative regulation of Hippo signaling in distinct Drosophila cellular contexts, but the contribution of Mob4/Phocein has yet to be defined (Ribeiro et al, 2010;Schulte et al, 2010;Sakuma et al, 2016;Zheng et al, 2017;Neisch et al, 2017;Gil-Ranedo et al, 2019). Mob4/Phocein proteins have been shown to bind directly to STE20 kinases in both fly and mammalian cells (Ribeiro et al, 2010;Couzens et al, 2017;Chen et al, 2018), but it is unclear if Mob4/Phocein is required to recruit GCK-type STE20 kinases to the STRIPAK complex.…”

Section: The Stripak Complex Is a Negative Regulator Of Hippo Signalingmentioning

confidence: 99%

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Mob Family Proteins: Regulatory Partners in Hippo and Hippo-Like Intracellular Signaling Pathways

Duhart

Raftery

2020

Front. Cell Dev. Biol.

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Studies in yeast first delineated the function of Mob proteins in kinase pathways that regulate cell division and shape; in multicellular eukaryotes Mobs regulate tissue growth and morphogenesis. In animals, Mobs are adaptors in Hippo signaling, an intracellular signal-transduction pathway that restricts growth, impacting the development and homeostasis of animal organs. Central to Hippo signaling are the Nuclear Dbf2-Related (NDR) kinases, Warts and LATS1 and LATS2, in flies and mammals, respectively. A second Hippo-like signaling pathway has been uncovered in animals, which regulates cell and tissue morphogenesis. Central to this emergent pathway are the NDR kinases, Tricornered, STK38, and STK38L. In Hippo signaling, NDR kinase activation is controlled by three activating interactions with a conserved set of proteins. This review focuses on one co-activator family, the highly conserved, non-catalytic Mps1binder-related (Mob) proteins. In this context, Mobs are allosteric activators of NDR kinases and adaptors that contribute to assembly of multiprotein NDR kinase activation complexes. In multicellular eukaryotes, the Mob family has expanded relative to model unicellular yeasts; accumulating evidence points to Mob functional diversification. A striking example comes from the most sequence-divergent class of Mobs, which are components of the highly conserved Striatin Interacting Phosphatase and Kinase (STRIPAK) complex, that antagonizes Hippo signaling. Mobs stand out for their potential to modulate the output from Hippo and Hippo-like kinases, through their roles both in activating NDR kinases and in antagonizing upstream Hippo or Hippo-like kinase activity. These opposing Mob functions suggest that they coordinate the relative activities of the Tricornered/STK38/STK38L and Warts/LATS kinases, and thus have potential to assemble nodes for pathway signaling output. We survey the different facets of Mobdependent regulation of Hippo and Hippo-like signaling and highlight open questions that hinge on unresolved aspects of Mob functions.

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Section: The Stripak Complex Is a Negative Regulator Of Hippo Signalingmentioning

confidence: 99%

Section: The Stripak Complex Is a Negative Regulator Of Hippo Signalingmentioning

confidence: 99%

Mob Family Proteins: Regulatory Partners in Hippo and Hippo-Like Intracellular Signaling Pathways

Duhart

Raftery

2020

Front. Cell Dev. Biol.

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“…As ribbon synapses mediate transmission between IHCs and spiral ganglion neurons (SGNs), our results lead us to propose that striatin, a component of the STRIPAK complex that interacts with the tumor supressor protein APC, regulates interneuronal synapses. This finding is supported by the observation that the Drosophila striatin homolog, CKA, facilitates axonal transport of dense core vesicles and autophagosomes in a PP2A-dependent manner [34].…”

Section: Striatin Knockout Mice Display An Aberrant Ribbon Gradientmentioning

confidence: 67%

Striatin is required for hearing and affects inner hair cells and ribbon synapses

Ponniah

Taiber

Caspi

et al. 2020

Preprint

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Striatin, a subunit of the serine/threonine phosphatase PP2A, is a core member of the conserved striatin-interacting phosphatase and kinase (STRIPAK) complexes. The protein is expressed in the cell junctions between epithelial cells, which play a role in maintaining cell-cell junctional integrity. Since adhesion is crucial for the function of the mammalian inner ear, we examined the localization and function of striatin in the mouse cochlea. Our results show that in neonatal mice, striatin is specifically expressed in the cell-cell junctions of the inner hair cells, the receptor cells in the mammalian cochlea.Auditory brainstem response measurements of striatin-deficient mice indicated a progressive, high-frequency hearing loss, suggesting that striatin is essential for normal hearing. Moreover, scanning electron micrographs of the organ of Corti revealed a moderate degeneration of the outer hair cells in the middle and basal regions, concordant with the high-frequency hearing loss. Importantly, striatin-deficient mice show aberrant ribbon synapse maturation that may lead to the observed auditory impairment. Together, these results suggest a novel function for striatin in the mammalian auditory system. Medicine Grant for Collaborative Research (RL, RRA). We thank Ana Turchetti-Maia and Kevin Ohlemiller for their advice for EP recordings, Vered Holdengreber for help with electron microscopy, and Ronen Siman-Tov for help with the mice. Author contributions KBA and RRA conceived the project. RAL generated the Striatin knockout mice. PTNP designed and performed the genotyping, dissections of inner ears, ABR, SEM, confocal imaging, Western blots, and quantification of ribbon synapses. MR and ST performed the endocochlear potential experiments. ST and TK-B aided with dissections and SEM imaging analysis. MC and AAD aided with image analysis, experimental design and organizing the data. PTNP, ST, KBA, and RRA wrote the manuscript. KBA and RRA supervised the work.

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“…Unlike hippocampal or cortical neurons, which are typically isolated from embryonic or early postnatal rodents, DRG neurons can be isolated from mice of any age and grow robustly in culture following dissection. Importantly, the spatial enrichment of autophagosome biogenesis in the distal neurite observed in culture (Maday and Holzbaur, 2014;Maday et al, 2012) has been confirmed in C. elegans and Drosophila neurons in vivo (Neisch et al, 2017;Stavoe et al, 2016). Since impaired autophagy has been implicated in the pathogenesis of neurodegenerative diseases and age is the most relevant risk factor for neurodegenerative disease, we examined how autophagosome biogenesis rates change with age.…”

Section: Autophagosome Biogenesis At the Axon Terminal Of Neurites Dementioning

confidence: 85%

Expression of WIPI2B counteracts age-related decline in autophagosome biogenesis in neurons

Stavoe

Holzbaur

2018

Preprint

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SUMMARYAutophagy defects have been implicated in multiple late-onset neurodegenerative diseases. Since aging is the most common risk factor in neurodegeneration, we asked how autophagy is modulated in aging neurons. We compared the dynamics of autophagosome biogenesis in neurons from young adult and aged mice, identifying a significant decrease in biogenesis during aging. Autophagosome assembly kinetics are disrupted, with frequent production of stalled isolation membranes in neurons from aged mice; these precursors failed to resolve into LC3-positive autophagosomes. We did not detect alterations in the initial induction/nucleation steps of autophagosome formation. However, we found that the transmembrane protein Atg9 remained aberrantly associated with stalled isolation membranes, suggesting a specific disruption in the WIPI-dependent retrieval of Atg9. Depletion of WIPI2 from young neurons was sufficient to induce a similar deficit. Further, exogenous expression of WIPI2 in neurons from aged mice was sufficient to restore autophagosome biogenesis to the rates seen in neurons from young adult mice, suggesting a novel therapeutic target for age-associated neurodegeneration.

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A STRIPAK complex mediates axonal transport of autophagosomes and dense core vesicles through PP2A regulation

Abstract: The regulation of cargo transport within neurons is not well understood. Neisch et al. use Drosophila genetics to identify a multiprotein STRIPAK complex required for autophagosome and dense core vesicle transport in neurons. PP2A activity within the complex is necessary for transport.

Cited by 88 publications

References 94 publications

Mob Family Proteins: Regulatory Partners in Hippo and Hippo-Like Intracellular Signaling Pathways

Mob Family Proteins: Regulatory Partners in Hippo and Hippo-Like Intracellular Signaling Pathways

Striatin is required for hearing and affects inner hair cells and ribbon synapses

Expression of WIPI2B counteracts age-related decline in autophagosome biogenesis in neurons

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