Microtubule +TIPs at a glance

Akhmanova, Anna; Steinmetz, Michel O.

doi:10.1242/jcs.062414

Cited by 247 publications

(241 citation statements)

References 80 publications

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“…EB proteins have been characterized as core +TIPs, organizing a molecular complex around growing MT plus-ends that dynamically explore the cytoplasm and interact with organelles and the cell cortex (21). We have found that EB proteins have a distinct behavior in the AIS, in contrast to their +TIP role in other neuronal compartments.…”

Section: Discussionmentioning

confidence: 94%

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End-binding proteins EB3 and EB1 link microtubules to ankyrin G in the axon initial segment

Leterrier

Vacher

Fache

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

148

152

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The axon initial segment (AIS) plays a key role in maintaining the molecular and functional polarity of the neuron. The relationship between the AIS architecture and the microtubules (MTs) supporting axonal transport is unknown. Here we provide evidence that the MT plus-end-binding (EB) proteins EB1 and EB3 have a role in the AIS in addition to their MT plus-end tracking protein behavior in other neuronal compartments. In mature neurons, EB3 is concentrated and stabilized in the AIS. We identified a direct interaction between EB3/EB1 and the AIS scaffold protein ankyrin G (ankG). In addition, EB3 and EB1 participate in AIS maintenance, and AIS disassembly through ankG knockdown leads to cell-wide up-regulation of EB3 and EB1 comets. Thus, EB3 and EB1 coordinate a molecular and functional interplay between ankG and the AIS MTs that supports the central role of ankG in the maintenance of neuronal polarity. N eurons are highly polarized cells that rely on microtubules (MTs) for maintenance of their architecture and long-range polarized trafficking (1). MTs supporting axonal transport travel through the axon initial segment (AIS), a compartment that is essential for the generation of action potentials (2) and the maintenance of neuronal polarity (3). Generation of action potentials depends on the concentration of voltage-gated sodium (Nav) and potassium channels at the AIS, which are tethered at the plasma membrane via their interaction with ankyrin G (ankG (4-7). ankG, in turn, is linked to the actin cytoskeleton via βIV-spectrin and organizes AIS formation by recruiting membrane proteins and βIV-spectrin to the nascent AIS (3).The AIS maintains neuronal polarity by forming a diffusion barrier for membrane constituents at the cell surface (4,8,9) and also by dampening intracellular diffusion and vesicular transport through the AIS (10). Both phenomena depend on ankG, because depletion of ankG results in the disappearance of AIS and the acquisition of dendritic identity by the proximal axon (11,12). However, the molecular role of ankG in the intracellular AIS organization is still unknown. The dependence of the AIS intracellular filter on ankG (10) and the disorganization of MT bundles in the AIS of Purkinje cells from ankG-deficient mice (12) suggest an unknown link between ankG and MTs in the AIS.The end-binding (EB) proteins family, composed of three members (EB1-3), has been described as plus-end-tracking proteins (+TIPs) that coordinate a network of dynamic proteins on the growing MT plus-ends (13). In neurons, EB1 has been implicated in axonal transport (14, 15), whereas EB3 has been characterized as a molecular link between MTs and the actin cytoskeleton (16, 17). We hypothesized that EB proteins could have a role in the AIS via interaction with the ankG/βIV-spectrin scaffold. We first found that EB3 is accumulated and stabilized in the AIS of mature neurons. Both EB3 and EB1 bind to ankG and participate in the maintenance of the AIS scaffold. Reciprocally, altering neuronal polarity through ankG knockdown in...

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Section: Discussionmentioning

confidence: 94%

“…4A). The EBH domain contains a polar rim followed by a hydrophobic pocket that is important for the binding of EB protein-interacting +TIPs (21). We first evaluated the ability of truncated EB3 constructs to interact with ankG in SPR experiments.…”

Section: Ankg Binds To the End-binding Homology Domain Hydrophobicmentioning

confidence: 99%

End-binding proteins EB3 and EB1 link microtubules to ankyrin G in the axon initial segment

Leterrier

Vacher

Fache

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

148

152

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“…MT-end dynamics, with rapid growth by a/b tubulin heterodimer subunit addition or shrinkage by subunit loss, can determine polymer length, which can be further modulated by MT-interacting proteins that stabilize or destabilize MTs, such as microtubule-associated proteins (MAPs), MT plus-end-tracking proteins (?TIPS) and bundling/depolymerising motors [1][2][3][4][5][6]. In parallel, a lot has been learned about additional mechanisms underlying MT plasticity.…”

Section: Introductionmentioning

confidence: 99%

A novel family of katanin-like 2 protein isoforms (KATNAL2), interacting with nucleotide-binding proteins Nubp1 and Nubp2, are key regulators of different MT-based processes in mammalian cells

Ververis

Christodoulou

Christoforou

et al. 2015

Cell. Mol. Life Sci.

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Katanins are microtubule (MT)-severing AAA proteins with high phylogenetic conservation throughout the eukaryotes. They have been functionally implicated in processes requiring MT remodeling, such as spindle assembly in mitosis and meiosis, assembly/disassembly of flagella and cilia and neuronal morphogenesis. Here, we uncover a novel family of katanin-like 2 proteins (KAT-NAL2) in mouse, consisting of five alternatively spliced isoforms encoded by the Katnal2 genomic locus. We further demonstrate that in vivo these isoforms are able to interact with themselves, with each other and moreover directly and independently with MRP/MinD-type P-loop NTPases Nubp1 and Nubp2, which are integral components of centrioles, negative regulators of ciliogenesis and implicated in centriole duplication in mammalian cells. We find KATNAL2 localized on interphase MTs, centrioles, mitotic spindle, midbody and the axoneme and basal body of sensory cilia in cultured murine cells. shRNAi of Katnal2 results in inefficient cytokinesis and severe phenotypes of enlarged cells and nuclei, increased numbers of centrioles and the manifestation of aberrant multipolar mitotic spindles, mitotic defects, chromosome bridges, multinuclearity, increased MT acetylation and an altered cell cycle pattern. Silencing or stable overexpression of KATNAL2 isoforms drastically reduces ciliogenesis. In conclusion, KATNAL2s are multitasking enzymes involved in the same cell type in critically important processes affecting cytokinesis, MT dynamics, and ciliogenesis and are also implicated in cell cycle progression.

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“…18 It is a MT rescue factor residing on growing (plus) ends of MTs. 5 At prometaphase of mitosis, CLIP1 links the outer part of unattached kinetochores to MT plus ends.…”

Section: Discussionmentioning

confidence: 99%

A defect in the CLIP1 gene (CLIP-170) can cause autosomal recessive intellectual disability

Larti¹,

Kahrizi²,

Musante³

et al. 2014

Eur J Hum Genet

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In the context of a comprehensive research project, investigating novel autosomal recessive intellectual disability (ARID) genes, linkage analysis based on autozygosity mapping helped identify an intellectual disability locus on Chr.12q24, in an Iranian family (LOD score ¼ 3.7). Next-generation sequencing (NGS) following exon enrichment in this novel interval, detected a nonsense mutation (p.Q1010*) in the CLIP1 gene. CLIP1 encodes a member of microtubule (MT) plus-end tracking proteins, which specifically associates with the ends of growing MTs. These proteins regulate MT dynamic behavior and are important for MT-mediated transport over the length of axons and dendrites. As such, CLIP1 may have a role in neuronal development. We studied lymphoblastoid and skin fibroblast cell lines established from healthy and affected patients. RT-PCR and western blot analyses showed the absence of CLIP1 transcript and protein in lymphoblastoid cells derived from affected patients. Furthermore, immunofluorescence analyses showed MT plus-end staining only in fibroblasts containing the wild-type (and not the mutant) CLIP1 protein. Collectively, our data suggest that defects in CLIP1 may lead to ARID.

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Microtubule +TIPs at a glance

Cited by 247 publications

References 80 publications

End-binding proteins EB3 and EB1 link microtubules to ankyrin G in the axon initial segment

End-binding proteins EB3 and EB1 link microtubules to ankyrin G in the axon initial segment

A novel family of katanin-like 2 protein isoforms (KATNAL2), interacting with nucleotide-binding proteins Nubp1 and Nubp2, are key regulators of different MT-based processes in mammalian cells

A defect in the CLIP1 gene (CLIP-170) can cause autosomal recessive intellectual disability

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