Casein Kinase 1δ Is an APC/CCdh1 Substrate that Regulates Cerebellar Granule Cell Neurogenesis

Penas, Clara; Govek, Eve Ellen; Yin, Fei; Ramachandran, Vimal; Daniel, Mark; Wang, Weiping; Maloof, Marie E.; Rahaim, Ronald J.; Bibian, Mathieu; Kawauchi, Daisuke; Finkelstein, David; Han, Jeng‐Liang; Long, Jun; Li, Bin; Robbins, David J.; Malumbres, Marcos; Roussel, Martine F.; Roush, William; Hatten, Mary E.; Ayad, Nagi G.

doi:10.1016/j.celrep.2015.03.016

Cited by 32 publications

(41 citation statements)

References 66 publications

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“…Knockdown of CK1δ by siRNA or pharmacologically by small molecule inhibitors leads to cell cycle arrest in granule neuron progenitors, suggesting that CK1δ promotes the proliferation of granule neuron progenitors. Cdh1-APC triggers the ubiquitination and consequent degradation of CK1δ in granule neuron progenitors (Penas et al 2015), suggesting that Cdh1-APC might promote cell cycle exit and consequent granule neuron differentiation. Surprisingly, however, conditional knockout of Cdh1 in granule neuron progenitors fails to alter the development of the mouse cerebellum even though this leads to increased levels of CK1δ in these cells (Penas et al 2015).…”

Section: Control Of Neurogenesis and Gliogenesis By Cdh1-apcmentioning

confidence: 99%

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A decade of the anaphase-promoting complex in the nervous system

Huang

Bonni

2016

Genes Dev.

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Control of protein abundance by the ubiquitin-proteasome system is essential for normal brain development and function. Just over a decade ago, the first post-mitotic function of the anaphase-promoting complex, a major cell cycle-regulated E3 ubiquitin ligase, was discovered in the control of axon growth and patterning in the mammalian brain. Since then, a large number of studies have identified additional novel roles for the anaphase-promoting complex in diverse aspects of neuronal connectivity and plasticity in the developing and mature nervous system. In this review, we discuss the functions and mechanisms of the anaphase-promoting complex in neurogenesis, glial differentiation and migration, neuronal survival and metabolism, neuronal morphogenesis, synapse formation and plasticity, and learning and memory. We also provide a perspective on future investigations of the anaphase-promoting complex in neurobiology.Protein degradation regulates diverse biological processes in the developing and mature nervous system. Spatial and temporal control of protein turnover and abundance influences distinct stages of neural development and function from neurogenesis and neuronal morphogenesis to synapse formation and pruning to plasticity and learning (Hegde and Upadhya 2007;Yi and Ehlers 2007;Segref and Hoppe 2009;Yamada et al. 2013). Protein degradation by the proteasome requires ubiquitination, which is mediated by the sequential action of an E1 ubiquitin-activating enzyme, E2 ubiquitin-conjugating enzyme, and E3 ubiquitin ligase (Hershko and Ciechanover 1992;Scheffner et al. 1995;Ciechanover 2005;Hershko 2005;Weissman et al.

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Section: Control Of Neurogenesis and Gliogenesis By Cdh1-apcmentioning

confidence: 99%

“…3A; Penas et al 2015). Knockdown of CK1δ by siRNA or pharmacologically by small molecule inhibitors leads to cell cycle arrest in granule neuron progenitors, suggesting that CK1δ promotes the proliferation of granule neuron progenitors.…”

Section: Control Of Neurogenesis and Gliogenesis By Cdh1-apcmentioning

confidence: 99%

A decade of the anaphase-promoting complex in the nervous system

Huang

Bonni

2016

Genes Dev.

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“…Furthermore, it has been shown that casein kinase 1 (ck 1) δ is an APC/C-Cdh1 substrate and that it regulates neurogenesis in cerebellar granule cells [32]. The ck 1 family is highly conserved in eukaryotes and controls a broad spectrum of biological processes, e.g., circadian rhythms, signal transduction, apoptosis, and neurite outgrowth.…”

Section: Apc/c-cdh1 and Neurogenesismentioning

confidence: 99%

New Functions of APC/C Ubiquitin Ligase in the Nervous System and Its Role in Alzheimer’s Disease

Fuchsberger

Lloret

Viña

2017

IJMS

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The E3 ubiquitin ligase Anaphase Promoting Complex/Cyclosome (APC/C) regulates important processes in cells, such as the cell cycle, by targeting a set of substrates for degradation. In the last decade, APC/C has been related to several major functions in the nervous system, including axon guidance, synaptic plasticity, neurogenesis, and neuronal survival. Interestingly, some of the identified APC/C substrates have been related to neurodegenerative diseases. There is an accumulation of some degradation targets of APC/C in Alzheimer’s disease (AD) brains, which suggests a dysregulation of the protein complex in the disorder. Moreover, recently evidence has been provided for an inactivation of APC/C in AD. It has been shown that oligomers of the AD-related peptide, Aβ, induce degradation of the APC/C activator subunit cdh1, in vitro in neurons in culture and in vivo in the mouse hippocampus. Furthermore, in the AD mouse model APP/PS1, lower cdh1 levels were observed in pyramidal neurons in CA1 when compared to age-matched wildtype mice. In this review, we provide a complete list of APC/C substrates that are involved in the nervous system and we discuss their functions. We also summarize recent studies that show neurobiological effects in cdh1 knockout mouse models. Finally, we discuss the role of APC/C in the pathophysiology of AD.

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“…5 Utilizing a cell based screening approach where we expressed Wee1-luciferase in HeLa cells and incubated the transfected cells with small molecule inhibitors, we discovered kinase inhibitors that were selective for Casein kinase (CK)1. 6,7 Using both biochemical and genetic studies we then demonstrated that CK1 and GSK3 phosphorylate Wee1 to target it for destruction. 6,7 In a similar manner, using a p27 Kip1 -luciferase fusion construct we demonstrated that PKCa phosphorylates p27 Kip1 and affects its degradation rate.…”

Section: Introductionmentioning

confidence: 99%

“…6,7 Using both biochemical and genetic studies we then demonstrated that CK1 and GSK3 phosphorylate Wee1 to target it for destruction. 6,7 In a similar manner, using a p27 Kip1 -luciferase fusion construct we demonstrated that PKCa phosphorylates p27 Kip1 and affects its degradation rate. 8 One of the main conclusions from these studies is that parallel screening of luciferase fusion proteins incubated with small molecules can uncover upstream modulators of a specific substrate's turnover.…”

Section: Introductionmentioning

confidence: 99%

A cell based screening approach for identifying protein degradation regulators

et al. 2017

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Cellular transitions are achieved by the concerted actions of regulated degradation pathways. In the case of the cell cycle, ubiquitin mediated degradation ensures unidirectional transition from one phase to another. For instance, turnover of the cell cycle regulator cyclin B1 occurs after metaphase to induce mitotic exit. To better understand pathways controlling cyclin B1 turnover, the N-terminal domain of cyclin B1 was fused to luciferase to generate an N-cyclin B1-luciferase protein that can be used as a reporter for protein turnover. Prior studies demonstrated that cell-based screens using this reporter identified small molecules inhibiting the ubiquitin ligase controlling cyclin B1-turnover. Our group adapted this approach for the G2-M regulator Wee1 where a Wee1-luciferase construct was used to identify selective small molecules inhibiting an upstream kinase that controls Wee1 turnover. In the present study we present a screening approach where cell cycle regulators are fused to luciferase and overexpressed with cDNAs to identify specific regulators of protein turnover. We overexpressed approximately 14,000 cDNAs with the N-cyclin B1-luciferase fusion protein and determined its steadystate level relative to other luciferase fusion proteins. We identified the known APC/C regulator Cdh1 and the F-box protein Fbxl15 as specific modulators of N-cyclin B1-luciferase steady-state levels and turnover. Collectively, our studies suggest that analyzing the steady-state levels of luciferase fusion proteins in parallel facilitates identification of specific regulators of protein turnover.

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Casein Kinase 1δ Is an APC/CCdh1 Substrate that Regulates Cerebellar Granule Cell Neurogenesis

Cited by 32 publications

References 66 publications

A decade of the anaphase-promoting complex in the nervous system

A decade of the anaphase-promoting complex in the nervous system

New Functions of APC/C Ubiquitin Ligase in the Nervous System and Its Role in Alzheimer’s Disease

A cell based screening approach for identifying protein degradation regulators

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