Anterograde Transport of TrkB in Axons Is Mediated by Direct Interaction with Slp1 and Rab27

Arimura, Nariko; Kimura, Toshihide; Nakamuta, Shinichi; Taya, Shinichiro; Funahashi, Yasuhiro; Hattori, Atsushi; Shimada, Akiko; Ménager, Céline; Kawabata, Saeko; Fujii, Kayo; Iwamatsu, Akihiro; Segal, Rosalind A.; Fukuda, Mitsunori; Kaibuchi, Kozo

doi:10.1016/j.devcel.2009.03.005

Cited by 182 publications

(186 citation statements)

References 43 publications

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“…16). Rab27A and Rab27B associate with kinesin-1 to regulate axonal transport of neurotrophin receptor-containing vesicles 17 . Members of the ADP-ribosylation factor (Arf) also regulate membrane traffic and organelle structure by recruiting cargo-sorting coat proteins, modulating membrane lipid composition and interacting with regulators of other G proteins 18,19 .…”

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confidence: 99%

Arl3 and LC8 regulate dissociation of dynactin from dynein

et al. 2014

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Cytoplasmic dynein acts as a motor for the intracellular retrograde motility of vesicles and organelles along microtubules. However, the regulatory mechanism underlying release of dynactin bound cargoes from dynein motor remains largely unknown. Here we report that ADP-ribosylation factor-like 3 (Arl3) and dynein light chain LC8 induce dissociation of dynactin from dynein. Immunoprecipitation and microtubule pull-down assays revealed that Arl3(Q71L) and LC8 facilitated detachment of dynactin from dynein. We also demonstrated Arl3(Q71L) or LC8-mediated dynactin release from a dynein-dynactin complex through trace experiments using quantum dot (Qdot)-conjugated proteins. Furthermore, we disclosed interactions of Arl3 and LC8 with dynactin and dynein, respectively, by live-cell imaging. Finally, knockdown (KD) of Arl3 and LC8 by siRNA induced abnormal localizations of dynein, dynactin and related organelles. Our findings uncovered the surprising functional relevance of GTP-bound Arl3 and LC8 for the unloading regulation of dynactin-bound cargo from dynein motor.

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confidence: 99%

Arl3 and LC8 regulate dissociation of dynactin from dynein

et al. 2014

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“…Notably, we demonstrate here the PIPP growth cone localization is CRMP2 dependent, as revealed by decreased PIPP staining in the growth cones of CRMP2 knockdown cells. This suggests CRMP2 connects PIPP to Kinesin-1, thus acting as a cargo adaptor as reported for tubulin heterodimers, Sra-1⅐WAVE1, and TrkB⅐Slp1 complexes (35)(36)(37).…”

Section: Discussionmentioning

confidence: 95%

“…CRMP2 and PIPP Exhibit Opposing Roles in Axon Selection and Elongation-CRMP2 promotes neurite extension by multiple mechanisms, including binding and stabilizing tubulin at the plus ends of microtubules (56,57), microtubule-based anterograde transport of tubulin heterodimers, the Sra-1⅐WAVE1 complex, and the Slp1⅐TrkB receptor complex to the distal part of the neurite via directly binding KLC (35)(36)(37) and regulation of anterograde transport. CRMP2 also inhibits retrograde transport (47) and links endocytic regulatory proteins to dynein (35)(36)(37).…”

Section: Discussionmentioning

confidence: 99%

“…CRMP2 also inhibits retrograde transport (47) and links endocytic regulatory proteins to dynein (35)(36)(37). In PC12 cells, used here as a model of early neurite elongation, we have shown CRMP2 and PIPP knockdown induce strikingly opposite phenotypes in terms of neurite extension, and localization of CRMP2 cargo WAVE1, and binding partner Kinesin-1 to the growth cone.…”

Section: Discussionmentioning

confidence: 99%

“…CRMP2-dependent neurite extension is in part mediated by Kinesin-1-dependent transport of tubulin, Sra-1/WAVE1, and TrkB to the growth cone (35)(36)(37). CRMP2 is essential for growth cone localization of these effectors, as it links Sra-1/ WAVE1 to Kinesin-1.…”

Section: Y2h Screening Identifies ␤Ii Tubulin and Crmp1 As Pippbindinmentioning

confidence: 99%

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Identification of a Proline-rich Inositol Polyphosphate 5-Phosphatase (PIPP)·Collapsin Response Mediator Protein 2 (CRMP2) Complex That Regulates Neurite Elongation

Astle

Ooms

Cole

et al. 2011

Journal of Biological Chemistry

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Neuron polarization is essential for the formation of one axon and multiple dendrites, establishing the neuronal circuitry. Phosphoinositide 3-kinase (PI3K) signaling promotes axon selection and elongation. Here we report in hippocampal neurons siRNA knockdown of the proline-rich inositol polyphosphate 5-phosphatase (PIPP), which degrades PI3K-generated PtdIns(3,4,5)P 3 , results in multiple hyperelongated axons consistent with a polarization defect. We identify collapsin response mediator protein 2 (CRMP2), which regulates axon selection by promoting WAVE1 delivery via Kinesin-1 motors to the axon growth cone, as a PIPP-interacting protein by Y2H screening, direct binding studies, and coimmunoprecipitation of an endogenous PIPP, CRMP2, and Kinesin-1 complex from brain lysates. The C-terminal growth cone-targeting domain of PIPP facilitates its interaction with CRMP2. PIPP growth cone localization is CRMP2-dependent. PIPP knockdown in PC12 cells promotes neurite elongation, WAVE1 and Kinesin-1 growth cone localization, whereas knockdown of CRMP2 exhibits the opposite phenotype, with shorter neurites and decreased WAVE1/Kinesin-1 at the growth cone. In contrast, CRMP2 overexpression promotes neurite elongation, a phenotype rescued by full-length PIPP, or expression of the CRMP2-binding PIPP domain. Therefore this study identifies PIPP and CRMP2 exert opposing roles in promoting axon selection and neurite elongation and the complex between these proteins serves to regulate the localization of effectors that promote neurite extension.Neurons are highly polarized cells that contain one long axon, which transmits information, and multiple shorter dendrites, which receive information (1, 2). The formation of axon/ dendrite polarity is critical for normal brain function. Neurons form networks connecting via synapses to other neurons, by extending axons in a process of neurite outgrowth and elongation. An actin-rich area at the tip of extending neurites, called the growth cone, enables neurite extension. Many signaling and actin regulatory factors function at the growth cone to promote neurite outgrowth and extension (2).The phosphoinositide 3-kinase (PI3K)/Akt signaling pathway promotes both neuronal polarity and neurite extension. In response to nerve growth factor (NGF) stimulation PI3K phosphorylates PtdIns(4,5)P 2 3 to form PtdIns(3,4,5)P 3 , a lipid signal that promotes neurite differentiation (3). In elongating neurons PtdIns(3,4,5)P 3 activates Rho GTPases Cdc42 and Rac1 that in turn regulate growth cone actin dynamics facilitating growth cone advancement (4, 5). PtdIns(3,4,5)P 3 also binds and activates the serine/threonine kinase Akt, which phosphorylates numerous targets, including Tau, GSK3␤, Ezrin, and Pak1 to regulate neuronal polarity, neurite outgrowth, and elongation (6, 7). GSK3␤ is inactivated by Akt phosphorylation (8) in the nascent growth cone (7, 9, 10). GSK3␤ effectors include CRMP2 (11, 12) and adenomatous polyposis coli (10, 13), which promote microtubule polymerization in the nascent axon driv...

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The many disguises of the signalling endosome

2018

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Neurons are highly complex and polarised cells that must overcome a series of logistic challenges to maintain homeostasis across their morphological domains. A very clear example is the propagation of neurotrophic signalling from distal axons, where target‐released neurotrophins bind to their receptors and initiate signalling, towards the cell body, where nuclear and cytosolic responses are integrated. The mechanisms of propagation of neurotrophic signalling have been extensively studied and, eventually, the model of a ‘signalling endosome’, transporting activated receptors and associated complexes, has emerged. Nevertheless, the exact nature of this organelle remains elusive. In this Review, we examine the evidence for the retrograde transport of neurotrophins and their receptors in endosomes, outline some of their diverse physiological and pathological roles, and discuss the main interactors, morphological features and trafficking destinations of a highly flexible endosomal signalling organelle with multiple molecular signatures.

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Anterograde Transport of TrkB in Axons Is Mediated by Direct Interaction with Slp1 and Rab27

Cited by 182 publications

References 43 publications

Arl3 and LC8 regulate dissociation of dynactin from dynein

Arl3 and LC8 regulate dissociation of dynactin from dynein

Identification of a Proline-rich Inositol Polyphosphate 5-Phosphatase (PIPP)·Collapsin Response Mediator Protein 2 (CRMP2) Complex That Regulates Neurite Elongation

The many disguises of the signalling endosome

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