Cayman ataxia protein caytaxin is transported by kinesin along neurites through binding to kinesin light chains

Aoyama, Takane; Hata, Suguru; Nakao, Takeshi; Tanigawa, Yuka; Oka, Chio; Kawaichi, Masashi

doi:10.1242/jcs.048579

Cited by 47 publications

(52 citation statements)

References 31 publications

(51 reference statements)

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“…3B). This LEWD motif is similar to binding motifs described in other KLC-binding proteins (Aoyama et al, 2009;Dodding et al, 2011;Konecna et al, 2006;Schmidt et al, 2009). Analysis of the KLC-binding region of nesprin-4 also revealed the presence of the LEWD motif, though the flanking sequences were less conserved (Fig.…”

Section: Recruitment Of Exogenous Kif5b To the Nuclear Envelope Rescusupporting

confidence: 76%

Nesprins anchor kinesin-1 motors to the nucleus to drive nuclear distribution in muscle cells

Wilson

Holzbaur

2015

Journal of Cell Science

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During skeletal muscle development, nuclei move dynamically through myotubes in a microtubule-dependent manner, driven by the microtubule motor protein kinesin-1. Loss of kinesin-1 leads to improperly positioned nuclei in culture and in vivo. Two models have been proposed to explain how kinesin-1 functions to move nuclei in myotubes. In the cargo model, kinesin-1 acts directly from the surface of the nucleus, whereas in an alternative model, kinesin-1 moves nuclei indirectly by sliding anti-parallel microtubules. Here, we test the hypothesis that an ensemble of Kif5B motors acts from the nuclear envelope to distribute nuclei throughout the length of syncytial myotubes. First, using an inducible dimerization system, we show that controlled recruitment of truncated, constitutively active kinesin-1 motors to the nuclear envelope is sufficient to prevent the nuclear aggregation resulting from depletion of endogenous kinesin-1. Second, we identify a conserved kinesin light chain (KLC)-binding motif in the nuclear envelope proteins nesprin-1 and nesprin-2, and show that recruitment of the motor complex to the nucleus via this LEWD motif is essential for nuclear distribution. Together, our findings demonstrate that the nucleus is a kinesin-1 cargo in myotubes and that nesprins function as nuclear cargo adaptors. The importance of achieving and maintaining proper nuclear position is not restricted to muscle fibers, suggesting that the nesprin-dependent recruitment of kinesin-1 to the nuclear envelope through the interaction of a conserved LEWD motif with kinesin light chain might be a general mechanism for cell-typespecific nuclear positioning during development.

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Section: Recruitment Of Exogenous Kif5b To the Nuclear Envelope Rescusupporting

confidence: 76%

Nesprins anchor kinesin-1 motors to the nucleus to drive nuclear distribution in muscle cells

Wilson

Holzbaur

2015

Journal of Cell Science

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“…Functional studies of Drosophila Klc suggest that it is not important for normal mitochondrial distribution in photoreceptor axons (Glater et al, 2006) and that it is dispensable in the binding of kinesin to mitochondrial adaptor proteins (MacAskill et al, 2009;Wang and Schwarz, 2009). However, recent work on caytaxin, a protein implicated in human ataxia, has shown that it binds to Klc, associates with mitochondria and influences mitochondria distribution in cultured cell neurites (Aoyama et al, 2009). Although caytaxin might be unique to vertebrates, further investigation of the possibility that in some cells Klc can influence mitochondria as well as vesicle transport seems warranted.…”

Section: Regulation Of Axonal Mitochondria Transportmentioning

confidence: 99%

The axonal transport of mitochondria

Saxton¹,

Hollenbeck²

2012

Journal of Cell Science

632

397

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SummaryVigorous transport of cytoplasmic components along axons over substantial distances is crucial for the maintenance of neuron structure and function. The transport of mitochondria, which serves to distribute mitochondrial functions in a dynamic and non-uniform fashion, has attracted special interest in recent years following the discovery of functional connections among microtubules, motor proteins and mitochondria, and their influences on neurodegenerative diseases. Although the motor proteins that drive mitochondrial movement are now well characterized, the mechanisms by which anterograde and retrograde movement are coordinated with one another and with stationary axonal mitochondria are not yet understood. In this Commentary, we review why mitochondria move and how they move, focusing particularly on recent studies of transport regulation, which implicate control of motor activity by specific cell-signaling pathways, regulation of motor access to transport tracks and static microtubule-mitochondrion linkers. A detailed mechanism for modulating anterograde mitochondrial transport has been identified that involves Miro, a mitochondrial Ca 2+ -binding GTPase, which with associated proteins, can bind and control kinesin-1. Elements of the Miro complex also have important roles in mitochondrial fission-fusion dynamics, highlighting questions about the interdependence of biogenesis, transport, dynamics, maintenance and degradation.

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“…Many studies reported that caytaxin plays an important role in axonal transporting [65], glutamate synthesis [66], synaptic apoptosis, and neurodegenerative diseases [67]. By using coimmunoprecipitation and mass spectrum detection, our unpublished preliminary results showed that DAPK1 could also interact and phosphorylate caytaxin on serine 46 at the presynaptic area in the mice model of middle cerebral artery occlusion (MCAO).…”

Section: Dapk1 and Caytaxinmentioning

confidence: 85%

[P2–202]: Dapk1 Signaling Pathways in Stroke: From Mechanisms to Therapies

2017

Alzheimer's & Dementia

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Death-associated protein kinase 1 (DAPK1), a Ca 2+ /calmodulin (CaM)-dependent serine/threonine protein kinase, plays important roles in diverse apoptosis pathways not only in tumor suppression but also in neuronal cell death. The requirement of DAPK1 catalytic activity for its proposed cell functions and the elevation of catalytic activity of DAPK1 in injured neurons in models of neurological diseases, such as ischemia and epilepsy, validate that DAPK1 can be taken as a potential therapeutic target in these diseases. Recent studies show that DAPK1-NR2B, DAPK1-DANGER, DAPK1-p53, and DAPK1-Tau are currently known pathways in strokeinduced cell death, and blocking these cascades in an acute treatment effectively reduces neuronal loss. In this review, we focus on the role of DAPK1 in neuronal cell death after stroke. We hope to provide exhaustive summaries of relevant studies on DAPK1 signals involved in stroke damage. Therefore, disrupting DAPK1-relevant cell death pathway could be considered as a promising therapeutic approach in stroke.

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Cayman ataxia protein caytaxin is transported by kinesin along neurites through binding to kinesin light chains

Abstract: Supplementary material available online at

Cited by 47 publications

References 31 publications

Nesprins anchor kinesin-1 motors to the nucleus to drive nuclear distribution in muscle cells

Nesprins anchor kinesin-1 motors to the nucleus to drive nuclear distribution in muscle cells

The axonal transport of mitochondria

[P2–202]: Dapk1 Signaling Pathways in Stroke: From Mechanisms to Therapies

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