Effects of kinesin-5 inhibition on dendritic architecture and microtubule organization

Kahn, Olga I.; Sharma, Vandana; González-Billault, Christian; Baas, Peter W.

doi:10.1091/mbc.e14-08-1313

Cited by 60 publications

(66 citation statements)

References 62 publications

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“…While KIF11 has been considered to be an essential component in mitosis, there have been a number of reports suggesting that it also has a role outside of the mitotic cycle, including in the regulation of cell motility, axonal branching, and angiogenesis (15–20, 33, 34). A potential caveat to the interpretation of some of these studies, however, is that cell motility ceases during mitosis, when both the microtubule- and actin-based cytoskeletons are recruited to form mitotically important structures, including the spindle and the cytokinetic ring.…”

Section: Resultsmentioning

confidence: 99%

The mitotic kinesin KIF11 is a driver of invasion, proliferation, and self-renewal in glioblastoma

et al. 2015

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The proliferative and invasive nature of malignant cancers drives lethality. In glioblastoma, these two processes are presumed mutually exclusive and hence termed “go or grow”. Here, we identified a molecular target that shuttles between these disparate cellular processes—the molecular motor KIF11. Inhibition of KIF11 with a highly specific small molecule inhibitor stopped the growth of both the more treatment resistant glioblastoma tumor initiating cells (TICs, or cancer stem cells) as well as non-TICs and impeded tumor initiation and self-renewal of the TIC population. Targeting KIF11 also hit the other arm of the “go or grow” cell fate decision by reducing glioma cell invasion. Administration of a KIF11 inhibitor to mice bearing orthotopic glioblastoma prolonged their survival. In its role as a shared molecular regulator of cell growth and motility across intratumoral heterogeneity, KIF11 is a compelling target for glioblastoma.

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Section: Resultsmentioning

confidence: 99%

The mitotic kinesin KIF11 is a driver of invasion, proliferation, and self-renewal in glioblastoma

et al. 2015

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“…Our previous work indicated that increased chromosome missegregation and aneuploidy (Granic et al, 2010) in cells due to Ab(1-42) interfering with correct mitotic spindle formation through inhibiting the Eg5 microtubule motor (Borysov et al, 2011). Importantly, Eg5 is also involved in regulating the organization and stability of microtubules in axons and dendrites, and thus may also indirectly impact microtubule-dependent receptor trafficking (Nadar et al, 2008;Ari et al, 2014;Kahn et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, exogenously added Ab can enter cells from the medium. Indeed, we recently found that Ab(1-42) inhibits the activity of the microtubule-dependent motor protein Eg5/kinesin-5 (also known as KIF11), which regulates a number of different important microtubule-dependent functions in neuronal and non-neuronal cells, including chromosome segregation, growth cone turning, and microtubule organization in axons and dendrites that may also indirectly impact membrane trafficking (Baas, 1998;Ferhat et al, 1998;Nadar et al, 2008;Borysov et al, 2011;Ari et al, 2014;Kahn et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of the Motor Protein Eg5/Kinesin-5 in Amyloid β-Mediated Impairment of Hippocampal Long-Term Potentiation and Dendritic Spine Loss

Freund¹,

Gibson²,

Potter³

et al. 2016

Mol Pharmacol

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Alzheimer's disease (AD) is characterized by neurofibrillary tangles, amyloid plaques, and neurodegeneration. However, this pathology is preceded by increased soluble amyloid beta (Ab) 1242 oligomers that interfere with the glutamatergic synaptic plasticity required for learning and memory, including N-methyl-D-aspartate receptor (NMDAR)-dependent long-term potentiation (LTP). In particular, soluble Ab(1-42) acutely inhibits LTP and chronically causes synapse loss. Many mechanisms have been proposed for Ab-induced synaptic dysfunction, but we recently found that Ab(1-42) inhibits the microtubule motor protein Eg5/kinesin-5. Here we compared the impacts of Ab(1-42) and monastrol, a small-molecule Eg5 inhibitor, on LTP in hippocampal slices and synapse loss in neuronal cultures. Acute (20-minute) treatment with monastrol, like Ab, completely inhibited LTP at doses .100 nM. In addition, 1 nM Ab(1-42) or 50 nM monastrol inhibited LTP~5 0%, and when applied together caused complete LTP inhibition. At concentrations that impaired LTP, neither Ab(1-42) nor monastrol inhibited NMDAR synaptic responses until 60 minutes, when only~25% inhibition was seen for monastrol, indicating that NMDAR inhibition was not responsible for LTP inhibition by either agent when applied for only 20 minutes. Finally, 48 hours of treatment with either 0.5-1.0 mM Ab(1-42) or 1-5 mM monastrol reduced the dendritic spine/synapse density in hippocampal cultures up to a maximum of~40%, and when applied together at maximal concentrations, no additional spine loss resulted. Thus, monastrol can mimic and in some cases occlude the impact of Ab on LTP and synapse loss, suggesting that Ab induces acute and chronic synaptic dysfunction in part through inhibiting Eg5.

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“…Kinesin-5 is a very slow motor, roughly hundred times slower than cytoplasmic dynein, which acts as a brake on microtubule movements (83). Inhibiting kinesin-5 result in greater mobility of microtubules in the axon and an overall shift in the forces on the microtubule array (84). As a result, the axon grows faster and more readily enters environments that are inhibitory to axonal regeneration (85).…”

Section: Figmentioning

confidence: 99%

Signaling Over Distances

Saito

Cavalli

2016

Molecular & Cellular Proteomics

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Neurons are extremely polarized cells. Axon lengths often exceed the dimension of the neuronal cell body by several orders of magnitude. These extreme axonal lengths imply that neurons have mastered efficient mechanisms for long distance signaling between soma and synaptic terminal. These elaborate mechanisms are required for neuronal development and maintenance of the nervous system. Neurons can fine-tune long distance signaling through calcium wave propagation and bidirectional transport of proteins, vesicles, and mRNAs along microtubules. The signal transmission over extreme lengths also ensures that information about axon injury is communicated to the soma and allows for repair mechanisms to be engaged. This review focuses on the different mechanisms employed by neurons to signal over long axonal distances and how signals are interpreted in the soma, with an emphasis on proteomic studies. We also discuss how proteomic approaches could help further deciphering the signaling mechanisms operating over long distance in axons. Neurons have unique and highly polarized morphologies. The axon allows intracellular communication between the cell soma and the distantly located synaptic terminal. The extreme length of axons relative to the cell soma diameter poses great challenges for neuronal development, maintenance, and repair. Anterograde and retrograde axonal transport of proteins vesicles and RNA along the microtubule tracks in the axon is crucial to sustain the required signaling events underlying development and maintenance of the nervous system. The retrograde transport system is also used following axon injury to communicate information from the site of injury back to the soma. Communication between distant axon locations and the cell soma is also ensured by a more rapid signal encoded in calcium waves. Incoming signals from distant axon locations are interpreted by the soma to regulate gene expression for survival or repair. The neuronal epigenome is also influenced by incoming signals to appropriately coordinate transcriptional responses. In this review, we discuss the state of the field regarding the different mechanisms employed by neurons to signal intracellularly over long distances in axons and how signals are interpreted in the cell soma, with an emphasis on proteomic studies. We also discuss how the use of proteomics could further help in understanding long distance signaling system in axons. The communication employed by neurons to signal along dendrites has been reviewed in detail elsewhere (1) and will not be discussed here.Calcium Influx, Back Propagation, and Long Distance Effects-Alterations in axonal calcium levels affect multiple and diverse signaling events, including local protein synthesis and degradation. These local signals can have long distance effects. Axon injury provides a powerful system to study the role of calcium in axonal signaling, because injury-induced calcium influx in the axon triggers important downstream events at the injury site and the soma (Fig.

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Effects of kinesin-5 inhibition on dendritic architecture and microtubule organization

Cited by 60 publications

References 62 publications

The mitotic kinesin KIF11 is a driver of invasion, proliferation, and self-renewal in glioblastoma

The mitotic kinesin KIF11 is a driver of invasion, proliferation, and self-renewal in glioblastoma

Inhibition of the Motor Protein Eg5/Kinesin-5 in Amyloid β-Mediated Impairment of Hippocampal Long-Term Potentiation and Dendritic Spine Loss

Signaling Over Distances

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