GSK‐3β Phosphorylation of Cytoplasmic Dynein Reduces Ndel1 Binding to Intermediate Chains and Alters Dynein Motility

Gao, Feng; Hebbar, Sachin; Gao, Xu; Alexander, Michael P.; Pandey, J. P.; Walla, Michael D.; Cotham, William E.; King, Stephen J.; Smith, Deanna S.

doi:10.1111/tra.12304

Cited by 51 publications

(67 citation statements)

References 75 publications

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“…Pharmacological inhibition of GSK3b in hippocampal and sensory (dorsal root ganglion, DRG) neurons has been shown to stimulate the axonal transport of brain-derived neurotrophic factor (BDNF)-containing secretory vesicles, mitochondria, and acidic organelles [24,28]. Similar results are also seen in Drosophila larval segmental nerves carrying loss-of-function mutations in GSK3 [27].…”

Section: Key Figurementioning

confidence: 79%

“…These contrasting results may represent differences in the regulation of axonal transport between species. GSK3b directly phosphorylates dynein intermediate chain 1B (DIC1B) and 2C (DIC2C), leading to inhibition of the retrograde axonal transport of acidic organelles [28]. GSK3b-mediated phosphorylation of DIC1B was shown to reduce its interaction with Ndel1 and Lis1, which enhance dynein force production [31].…”

Section: Key Figurementioning

confidence: 99%

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Regulation of Axonal Transport by Protein Kinases

Gibbs

Greensmith

Schiavo

2015

Trends in Biochemical Sciences

107

102

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The intracellular transport of organelles, proteins, lipids, and RNA along the axon is essential for neuronal function and survival. This process, called axonal transport, is mediated by two classes of ATP-dependent motors, kinesins, and cytoplasmic dynein, which carry their cargoes along microtubule tracks. Protein kinases regulate axonal transport through direct phosphorylation of motors, adapter proteins, and cargoes, and indirectly through modification of the microtubule network. The misregulation of axonal transport by protein kinases has been implicated in the pathogenesis of several nervous system disorders. Here, we review the role of protein kinases acting directly on axonal transport and discuss how their deregulation affects neuronal function, paving the way for the exploitation of these enzymes as novel drug targets.

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Section: Key Figurementioning

confidence: 79%

Section: Key Figurementioning

confidence: 99%

Regulation of Axonal Transport by Protein Kinases

Gibbs

Greensmith

Schiavo

2015

Trends in Biochemical Sciences

107

102

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“…As Cdk5 and GSK3 kinases regulate Dynein 32,33 and because FEME carriers containing Shiga toxin rely on this microtubule motor for scission and retrograde trafficking 34,35 , a role for the kinases in regulating Dynein during FEME was explored. We confirmed that inhibiting Dynein (with either the small inhibitor Ciliobrevin D 36 or the overexpression of the p50 dynamitin subunit of the dynactin complex 37 ) blocked FEME carrier budding and β1AR endocytosis ( Supplementary Figure S5a-b ).…”

Section: Resultsmentioning

confidence: 99%

Cdk5 and GSK3β inhibit Fast Endophilin-Mediated Endocytosis

Ferreira

Casamento

Roas

et al. 2020

Preprint

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20Endocytosis mediates the cellular uptake of micronutrients and cell surface proteins. Parallel to 21 Clathrin-mediated endocytosis, additional Clathrin-independent endocytic routes exist, including fast 22 Endophilin-mediated endocytosis (FEME). The latter is not constitutively active but requires the 23 activation of selected receptors. In cell culture, however, the high levels of growth factors in the 24 regular culture media induce spontaneous FEME, which can be suppressed upon serum starvation. 25Thus, we predicted a role for protein kinases in this growth factor receptor-mediated regulation of 26 the pathway. Using chemical and genetic inhibition, we found that Cdk5 and GSK3β are negative 27 regulators of FEME. Their inhibition was sufficient to activate FEME promptly in resting cells and 28 boosted the production of endocytic carriers containing β1-adrenergic receptor, following 29 dobutamine addition. We established that the kinases suppress FEME at several levels. They control 30 Dynamin-1 and Dynein recruitment and sorting of cargo receptors such as Plexin A1 and ROBO1 into 31 FEME carriers. They do so by antagonizing the binding of Endophilin to Dynamin-1 as well as to 32 Collapsin response mediator protein 4 (CRMP4), a Plexin A1 adaptor. Cdk5 and GSK3β also hamper 33 the binding and recruitment of Dynein onto FEME carriers by Bin1. Interestingly, we found that 34 GSK3β binds to Endophilin, thus imposing a local regulation of FEME. Collectively, these findings 35 place the two kinases as key regulators of FEME, licensing cells for rapid uptake by the pathway only 36 upon when Cdk5 and GSK3β activity is low. 38 39Clathrin-mediated endocytosis (CME) is the major uptake pathway in resting cells 1,2 but additional Clathrin-40 independent endocytic (CIE) routes, including fast Endophilin-mediated endocytosis (FEME), perform 41 specific functions or internalize various cargoes 3,4 . FEME is not constitutively active but is triggered upon the 42 stimulation of selected cell surface receptors by their ligands 5 . These include G-protein coupled receptors 43 (e.g. β1-adrenergic receptor, hereafter β1AR), receptor tyrosine kinases (e.g. epidermal growth factor 44 receptor, EGFR) or cytokine receptors (e.g. Interleukin-2 receptor) 5 . In resting cells, FEME is primed by a 45 cascade of molecular events starting with active, GTP-loaded, Cdc42 recruiting CIP4/FBP17 that engage the 46 5'-phosphatase SHIP2 and Lamellipodin (Lpd). The latter then concentrates Endophilin into clusters on 47 discrete locations of the plasma membrane 6 . In absence of receptor activation, the clusters dissemble 48 quickly (after 5 to 15 sec) upon local recruitment of the Cdc42 GTPase-activating proteins RICH1, SH3BP1 49 or Oligophrenin 6 New priming cycles start nearby, constantly priming the plasma membrane for FEME. Upon 50 activation, receptors are quickly sorted into pre-existing Endophilin clusters that then bud to form FEME 51 carriers, which are Clathrin-negative, Endophilin-positive assemblies (EPAs) found in the cytosol. The en...

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“…GSK-3β has been reported to phosphorylate dynein intermediate chain (IC) at S87/ T88 in IC-1B and S88/T89 in IC-2C, which are the key sites for NDEL1 binding domain, leading to reduction of its interacting with NDEL1 [26]. Thus, the interaction of NDEL1 and dynein is negatively regulated by GSK-3β.…”

Section: Gsk-3β Regulates Mitochondrial Motilitymentioning

confidence: 99%

The Key Roles of GSK-3β in Regulating Mitochondrial Activity

Yang

Chen

Gao

et al. 2017

Cell Physiol Biochem

174

119

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Glycogen synthase kinase-3β (GSK-3β), a serine/threonine protein kinase, has been reported to show essential roles in molecular pathophysiology of many diseases. Mitochondrion is a dynamic organelle for producing cellular energy and determining cell fates. Stress-induced translocated GSK-3β may interact with mitochondrial proteins, including PI3K-Akt, PGC-1α, HK II, PKCε, components of respiratory chain, and subunits of mPTP. Mitochondrial pool of GSK-3β has been implicated in mediation of mitochondrial functions. GSK-3β exhibits the regulatory effects on mitochondrial biogenesis, mitochondrial bioenergetics, mitochondrial permeability, mitochondrial motility, and mitochondrial apoptosis. The versatile functions of GSK-3β might be associated with its wide range of substrates. Accumulative evidence demonstrates that GSK-3β inactivation may be potentially developed as the promising strategy in management of many diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). Intensive efforts have been made for exploring GSK-3β inhibitors. Natural products provide us a great source for screening new lead compounds in inactivation of GSK-3β. The key roles of GSK-3β in mediation of mitochondrial functions are discussed in this review.

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GSK‐3β Phosphorylation of Cytoplasmic Dynein Reduces Ndel1 Binding to Intermediate Chains and Alters Dynein Motility

Cited by 51 publications

References 75 publications

Regulation of Axonal Transport by Protein Kinases

Regulation of Axonal Transport by Protein Kinases

Cdk5 and GSK3β inhibit Fast Endophilin-Mediated Endocytosis

The Key Roles of GSK-3β in Regulating Mitochondrial Activity

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