Transport of PIP3 by GAKIN, a kinesin-3 family protein, regulates neuronal cell polarity

Horiguchi, Kaori; Hanada, Toshihiko; Fukui, Yoshihiro; Chishti, Athar H.

doi:10.1083/jcb.200604031

Cited by 147 publications

(163 citation statements)

References 51 publications

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“…We reported previously that PIP 3 seems to be transported toward the contact site . In fact, Horiguchi et al (2006) recently demonstrated that a complex of guanylate kinase-associated kinesin and a PIP 3 -interacting protein, PIP 3 BP, transports PIP 3 to the neurite end. The phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a lipid and protein phosphatase that functions in an opposite manner from PI3-kinase by dephosphorylating PIP 3 (Maehama and Dixon, 1998).…”

Section: Pi3-kinase/akt/gsk-3␤ Pathwaymentioning

confidence: 99%

Signaling Networks in Neuronal Polarization

Yoshimura¹,

Arimura²,

Kaibuchi

2006

J. Neurosci.

101

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A mature neuron is typically polarized both structurally and functionally, with a single long axon and several dendrites. Neuronal polarity is essential for unidirectional signal flow from somata or dendrites to axons. The initial event in establishing a polarized neuron is the specification of a single axon. Early in neuronal development, one immature neurite becomes differentiated from other neurites to form an axon. Although studies in the past two decades have yielded a catalog of structural, molecular, and functional differences between axons and dendrites, we are only now beginning to understand the molecular mechanisms involved in the establishment of neuronal polarity.In the last few years, neuronal polarity-regulating molecules have been revealed. There are two major signaling cascades in neuronal polarization. Several groups, including ours, reported that the phosphatidylinositol 3-kinase (PI3-kinase)/Akt/glycogen synthase kinase-3␤ (GSK-3␤)/collapsin response mediator protein-2 pathway is important for axon specification and elongation. Recent studies have revealed that the positive feedback loop composed of Rho family small GTPases and the Par3/Par6/atypical protein kinase C complex plays a role in the initial events of neuronal polarization downstream of PI3-kinase. Here, we discuss the roles of signaling molecules for axon specification. Key words: axon; neuronal polarity; PI3-kinase; GSK-3␤; CRMP-2; Par complex Processes of neuronal polarizationThe ability of neuronal cells to polarize is essential for organization of the nervous system. A model system for studying neuronal polarity, cultured hippocampal neurons, was pioneered by Craig and Banker (1994) Ͼ20 years ago. Cultured hippocampal neurons develop a single long axon and several shorter dendrites, which maintain their structural characteristics at the molecular level. During maturation, hippocampal neurons dramatically change their morphology. Dotti et al. (1988) precisely observed this differentiation process and divided the morphological events into five stages (Fig. 1). Shortly after attachment to the substratum, a neuron extends lamellipodia (stage 1). These protrusions then develop into several short immature neurites (stage 2). At this stage, neurons still appear to be unpolarized. All neurites alternate phases of elongation and retraction and are approximately equal in length. It is difficult to determine which neurite will become an axon. Next, one of the immature neurites rapidly grows into a long neurite, which soon acquires axonal characteristics (stage 3). A few days after the formation of the axon, the remaining neurites slowly elongate to become dendrites (stage 4). Typically, the axon and dendrites continue to mature and subsequently develop by 7 d after plating. Cultured neurons form synaptic contacts and establish a neuronal network (stage 5).Neuronal polarization occurs from stage 2 to stage 3. The first step in neuronal polarization is initial axon formation. The specification of the axon is thought to depend on its length...

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Section: Pi3-kinase/akt/gsk-3␤ Pathwaymentioning

confidence: 99%

Signaling Networks in Neuronal Polarization

Yoshimura¹,

Arimura²,

Kaibuchi

2006

J. Neurosci.

101

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“…6 A, B, D, E). This truncated form of kif13B has been used previously to demonstrate that kif13B transports Dlg1 to the tip of MDCK cell projections (Asaba et al, 2003) and PtdIns(3,4,5)P 3 (also known as PIP 3 ) to the tips of growing neurons through a PIP 3 BP (PIP 3 -binding protein) complex (Horiguchi et al, 2006). Following on the hypothesis that, in Schwann cells, kif13B transports Dlg1 at nodal-paranodal regions, first we quantified Dlg1 staining in myelinated fibers.…”

Section: Dlg1 Interacts With Kif13b and Sec8 In Schwann Cells In The mentioning

confidence: 99%

Dlg1, Sec8, and Mtmr2 Regulate Membrane Homeostasis in Schwann Cell Myelination

Bolis¹,

Coviello²,

Visigalli³

et al. 2009

Journal of Neuroscience

107

102

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How membrane biosynthesis and homeostasis is achieved in myelinating glia is mostly unknown. We previously reported that loss of myotubularin-related protein 2 (MTMR2) provokes autosomal recessive demyelinating Charcot-Marie-Tooth type 4B1 neuropathy, characterized by excessive redundant myelin, also known as myelin outfoldings. We generated a Mtmr2-null mouse that models the human neuropathy. We also found that, in Schwann cells, Mtmr2 interacts with Discs large 1 (Dlg1), a scaffold involved in polarized trafficking and membrane addition, whose localization in Mtmr2-null nerves is altered. We here report that, in Schwann cells, Dlg1 also interacts with kinesin 13B (kif13B) and Sec8, which are involved in vesicle transport and membrane tethering in polarized cells, respectively. Taking advantage of the Mtmr2-null mouse as a model of impaired membrane formation, we provide here the first evidence for a machinery that titrates membrane formation during myelination. We established Schwann cell/DRG neuron cocultures from Mtmr2-null mice, in which myelin outfoldings were reproduced and almost completely rescued by Mtmr2 replacement. By exploiting this in vitro model, we propose a mechanism whereby kif13B kinesin transports Dlg1 to sites of membrane remodeling where it coordinates a homeostatic control of myelination. The interaction of Dlg1 with the Sec8 exocyst component promotes membrane addition, whereas with Mtmr2, negatively regulates membrane formation. Myelin outfoldings thus arise as a consequence of the loss of negative control on the amount of membrane, which is produced during myelination.

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“…Various mechanisms have evolved to establish and maintain cellular polarity, which, in most cases, are based on asymmetrical distribution of specific proteins or on higher-order organization of cellular structures. Recently, the Par (Partition-defective) family of proteins has frequently been assigned an essential role in mammalian systems, notably in axon polarization (Benton and Johnston, 2003;Shi et al, 2003), but other protein families have also been implicated, namely, proteins in the PI 3 K-associated pathway (Horiguchi et al, 2006) and small GTPases (Wells et al, 2006). Despite increasing insight into the regulatory interactions of these proteins, some fundamental aspects still need to be resolved as, in most reports, the mechanisms through which polarization is achieved and maintained are not established.…”

Section: Introductionmentioning

confidence: 99%

Exclusion of a Proton ATPase from the Apical Membrane Is Associated with Cell Polarity and Tip Growth inNicotiana tabacumPollen Tubes

et al. 2008

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Polarized growth in pollen tubes results from exocytosis at the tip and is associated with conspicuous polarization of Ca2+, H+, K+, and Cl− -fluxes. Here, we show that cell polarity in Nicotiana tabacum pollen is associated with the exclusion of a novel pollen-specific H+-ATPase, Nt AHA, from the growing apex. Nt AHA colocalizes with extracellular H+ effluxes, which revert to influxes where Nt AHA is absent. Fluorescence recovery after photobleaching analysis showed that Nt AHA moves toward the apex of growing pollen tubes, suggesting that the major mechanism of insertion is not through apical exocytosis. Nt AHA mRNA is also excluded from the tip, suggesting a mechanism of polarization acting at the level of translation. Localized applications of the cation ionophore gramicidin A had no effect where Nt AHA was present but acidified the cytosol and induced reorientation of the pollen tube where Nt AHA was absent. Transgenic pollen overexpressing Nt AHA-GFP developed abnormal callose plugs accompanied by abnormal H+ flux profiles. Furthermore, there is no net flux of H+ in defined patches of membrane where callose plugs are to be formed. Taken together, our results suggest that proton dynamics may underlie basic mechanisms of polarity and spatial regulation in growing pollen tubes.

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Transport of PIP3 by GAKIN, a kinesin-3 family protein, regulates neuronal cell polarity

Cited by 147 publications

References 51 publications

Signaling Networks in Neuronal Polarization

Signaling Networks in Neuronal Polarization

Dlg1, Sec8, and Mtmr2 Regulate Membrane Homeostasis in Schwann Cell Myelination

Exclusion of a Proton ATPase from the Apical Membrane Is Associated with Cell Polarity and Tip Growth inNicotiana tabacumPollen Tubes

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