KIF21A-Mediated Axonal Transport and Selective Endocytosis Underlie the Polarized Targeting of NCKX2

Lee, Kyu-Hee; Lee, Jae Sung; Lee, Doyun; Seog, Dae Hyun; Lytton, Jonathan; Ho, Won Kyung; Lee, Suk Ho

doi:10.1523/jneurosci.6331-11.2012

Cited by 35 publications

(26 citation statements)

References 51 publications

(78 reference statements)

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“…In vitro, the KIF21A motor domain behaves similarly to that of Xklp1 – it reduces the MT growth rate and suppresses catastrophes (van der Vaart et al, 2013). There are also indications that in addition to controlling MT dynamics, KIF21A plays a role in membrane transport (Lee et al, 2012). All CFEOM1-associated mutations in KIF21A localize either to the motor domain or to a predicted short coiled-coil domain in the stalk region of the molecule, and each of them prevents the autoinhibitory interaction between these two elements (Bianchi et al, 2016; Cheng et al, 2014; van der Vaart et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Kinesin-4 KIF21B is a potent microtubule pausing factor

Riel

Rai

Bianchi

et al. 2017

eLife

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Microtubules are dynamic polymers that in cells can grow, shrink or pause, but the factors that promote pausing are poorly understood. Here, we show that the mammalian kinesin-4 KIF21B is a processive motor that can accumulate at microtubule plus ends and induce pausing. A few KIF21B molecules are sufficient to induce strong growth inhibition of a microtubule plus end in vitro. This property depends on non-motor microtubule-binding domains located in the stalk region and the C-terminal WD40 domain. The WD40-containing KIF21B tail displays preference for a GTP-type over a GDP-type microtubule lattice and contributes to the interaction of KIF21B with microtubule plus ends. KIF21B also contains a motor-inhibiting domain that does not fully block the interaction of the protein with microtubules, but rather enhances its pause-inducing activity by preventing KIF21B detachment from microtubule tips. Thus, KIF21B combines microtubule-binding and regulatory activities that together constitute an autonomous microtubule pausing factor.DOI: http://dx.doi.org/10.7554/eLife.24746.001

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Section: Introductionmentioning

confidence: 99%

Kinesin-4 KIF21B is a potent microtubule pausing factor

Riel

Rai

Bianchi

et al. 2017

eLife

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“…We have previously reported that dynamin-1-mediated endocytosis is involved in the low surface expression of NCKX2 in the somatodendritic region (Lee et al, 2012). Dynamin-1 is one of the key players in clathrin-mediated endocytosis.…”

Section: Resultsmentioning

confidence: 99%

“…Previously, based on studies of the decay phase of calcium transients, we have reported that NCKX activity is the major CCM at axon terminals but is not detectable in somatodendritic regions of central neurons (Kim et al, 2003, 2005; Lee et al, 2009). Furthermore, we have shown that the surface expression of NCKX2 is polarized to the axonal compartment (Lee et al, 2012) in cultured hippocampal neurons. This view is in disagreement with other studies, which showed the direct recording of NCKX current or Ca 2+ -influx via the reverse mode of NCKX in the somata of cortical neurons (Kiedrowski et al, 2004; Cuomo et al, 2008).…”

Section: Introductionmentioning

confidence: 91%

“…Indeed, we have previously reported that not only axon terminals but also somatodendritic regions are immunoreactive for NCKX2 in cultured hippocampal neurons under permeabilized conditions. Furthermore, suppression of endocytosis allowed the dendritic surface expression of NCKX2, suggesting that constitutive endocytosis of NCKX2 from somatodendritic compartments contributes to the axonal polarization of the NCKX2 activity (Lee et al, 2012). These previous findings prompted us to study the molecular mechanism regulating the surface expression of NCKX2 in dendrites of central neurons.…”

Section: Introductionmentioning

confidence: 99%

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Endocytosis of somatodendritic NCKX2 is regulated by Src family kinase-dependent tyrosine phosphorylation

Lee¹,

Ho²,

Lee³

2013

Front. Cell. Neurosci.

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We have previously reported that the surface expression of K+-dependent Na+/Ca2+ exchanger 2 (NCKX2) in the somatodendritic compartment is kept low by constitutive endocytosis, which results in the polarization of surface NCKX2 to the axon. Clathrin-mediated endocytosis is initiated by interaction of the μ subunit of adaptor protein complex 2 (AP-2) with the canonical tyrosine motif (YxxΦ) of a target molecule. We examined whether endocytosis of NCKX2 involves two putative tyrosine motifs (365YGKL and 371YDTM) in the cytoplasmic loop of NCKX2. Coimmunoprecipitation assay revealed that the 365YGKL motif is essential for the interaction with the μ subunit of AP-2 (AP2M1). Consistently, either overexpression of NCKX2-Y365A mutant or knockdown of AP2M1 in cultured hippocampal neurons significantly reduced the internalization of NCKX2 from the somatodendritic surface and thus abolished the axonal polarization of surface NCKX2. Next, we tested whether the interaction between the tyrosine motif and AP2M1 is regulated by phosphorylation of the 365th tyrosine residue (Tyr-365). Tyrosine phosphorylation of heterologously expressed NCKX2-WT, but not NCKX2-Y365A, was increased by carbachol (CCh) in PC-12 cells. The effect of CCh was inhibited by PP2, a Src family kinase (SFK) inhibitor. Moreover, PP2 facilitated the endocytosis of NCKX2 in both the somatodendritic and axonal compartments, suggesting that tyrosine phosphorylation of NCKX2 by SFK negatively regulates its endocytosis. Supporting this idea, activation of SFK enhanced the NCKX activity in the proximal dendrites of dentate granule cells (GCs). These results suggest that endocytosis of somatodendritic NCKX2 is regulated by SFK-dependent phosphorylation of Tyr-365.

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“…Mutations in the KIF21A stalk region have been shown to be the underlying cause of congenital fibrosis of the extraocular muscle type 1 (CFEOM1) (Yamada et al, 2003), which is associated with defects in the oculomotor nerve and results in an inability to move or raise the eyes. A recent study showed that knockdown of KIF21A causes the dysregulation of Ca 2+ at axonal boutons owing to inhibited transport of NCKX2, a K + -dependent Na + -exchanger that is involved in Ca 2+ clearance in the large axon terminals of central neurons (Lee et al, 2012). Moreover, a mutation in KIF1B-b, a kinesin-3 family member, was identified in CMT2 patients (Zhao et al, 2001).…”

Section: Journal Of Cell Sciencementioning

confidence: 99%

Microtubule-based transport – basic mechanisms, traffic rules and role in neurological pathogenesis

Franker

Hoogenraad

2013

Journal of Cell Science

181

170

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SummaryMicrotubule-based transport is essential for neuronal function because of the large distances that must be traveled by various building blocks and cellular materials. Recent studies in various model systems have unraveled several regulatory mechanisms and traffic rules that control the specificity, directionality and delivery of neuronal cargos. Local microtubule cues, opposing motor activity and cargoadaptors that regulate motor activity control microtubule-based transport in neurons. Impairment of intracellular transport is detrimental to neurons and has emerged as a common factor in several neurological disorders. Genetic approaches have revealed strong links between intracellular transport processes and the pathogenesis of neurological diseases in both the central and peripheral nervous system. This Commentary highlights recent advances in these areas and discusses the transport defects that are associated with the development of neurological diseases.

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KIF21A-Mediated Axonal Transport and Selective Endocytosis Underlie the Polarized Targeting of NCKX2

Cited by 35 publications

References 51 publications

Kinesin-4 KIF21B is a potent microtubule pausing factor

Kinesin-4 KIF21B is a potent microtubule pausing factor

Endocytosis of somatodendritic NCKX2 is regulated by Src family kinase-dependent tyrosine phosphorylation

Microtubule-based transport – basic mechanisms, traffic rules and role in neurological pathogenesis

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