Control of a Kinesin-Cargo Linkage Mechanism by JNK Pathway Kinases

Horiuchi, Dai; Collins, Catherine A.; Bhat, Pavan; Barkus, Rosemarie V.; DiAntonio, Aaron; Saxton, William M.

doi:10.1016/j.cub.2007.06.062

Cited by 145 publications

(146 citation statements)

References 31 publications

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“…In the latter role, it is conceivable that the Munc18-FEZ1 interaction serves to signal to the motor that a properly processed cargo has been loaded. The observation that the binding of Munc18 to FEZ1 is also phosphorylation-dependent offers a tantalizing possibility that such events may mediate loading/unloading of Stx trafficking vesicles to KIF5C as has been reported for other Kinesin adapters (4).…”

Section: Discussionmentioning

confidence: 96%

“…Deletion of this kinase phenocopies deletion of UNC-76. Indeed, phosphorylation-regulated interactions between cargo, adaptors, and kinesins have also been observed for other transport complexes such as the kinesin light chain/JIP1 (c-Jun N-terminal kinase-interacting protein 1) complex (4). This suggests that phosphorylation is a common mechanism for the regulation of kinesin-based transport complexes (5).…”

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confidence: 86%

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Phosphorylation-regulated axonal dependent transport of syntaxin 1 is mediated by a Kinesin-1 adapter

Chua

Butkevich

Worseck

et al. 2012

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

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Presynaptic nerve terminals are formed from preassembled vesicles that are delivered to the prospective synapse by kinesin-mediated axonal transport. However, precisely how the various cargoes are linked to the motor proteins remains unclear. Here, we report a transport complex linking syntaxin 1a (Stx) and Munc18, two proteins functioning in synaptic vesicle exocytosis at the presynaptic plasma membrane, to the motor protein Kinesin-1 via the kinesin adaptor FEZ1. Mutation of the FEZ1 ortholog UNC-76 in Caenorhabditis elegans causes defects in the axonal transport of Stx. We also show that binding of FEZ1 to Kinesin-1 and Munc18 is regulated by phosphorylation, with a conserved site (serine 58) being essential for binding. When expressed in C. elegans, wild-type but not phosphorylationdeficient FEZ1 (S58A) restored axonal transport of Stx. We conclude that FEZ1 operates as a kinesin adaptor for the transport of Stx, with cargo loading and unloading being regulated by protein kinases. T he formation and maintenance of presynaptic boutons are intricate but highly efficient processes during which the machinery for exocytosis and recycling of synaptic vesicles is assembled from preformed units. These units are delivered to the nascent synapse via molecular motor proteins of the kinesin superfamily (reviewed in Ref. 1).Although Kinesin-3 appears to be the main motor transporting synaptic vesicle precursors, recent evidence suggests that Kinesin-1 (KIF5) is also involved. In Drosophila, deletion of UNC-76/ fasciculation and elongation protein zeta 1 (FEZ1), a specific adaptor for Kinesin-1, left synaptic vesicles stranded in the axon (2, 3), showing that Kinesin-1 is needed at least during later phases of axonal transport. Transport of the synaptic vesicle protein synaptotagmin by the UNC-76/Kinesin-1 complex requires phosphorylation of UNC-76 by the UNC-51/ATG1 kinase, a prerequisite for UNC-76 to bind synaptotagmin (3). Deletion of this kinase phenocopies deletion of UNC-76. Indeed, phosphorylation-regulated interactions between cargo, adaptors, and kinesins have also been observed for other transport complexes such as the kinesin light chain/JIP1 (c-Jun N-terminal kinase-interacting protein 1) complex (4). This suggests that phosphorylation is a common mechanism for the regulation of kinesin-based transport complexes (5).Less is known about the involvement of Kinesin-1 in the transport of other classes of synaptic precursor vesicles. Transport of syntaxin 1a (Stx), an essential component of the exocytotic release apparatus residing in the presynaptic plasma membrane, is clearly distinct from synaptic vesicle precursors and appears to involve a complex between Kinesin-1 and the Stx-binding protein syntabulin (6, 7). Down-regulation or expression of dominant-negative syntabulin reduces but does not abolish membrane delivery of Stx, indicating the existence of other transport mechanisms (6). Moreover, proper intracellular trafficking of Stx and its function in exocytosis depends on Munc18 coexpression (8-14). Stx tra...

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Section: Discussionmentioning

confidence: 96%

mentioning

confidence: 86%

Phosphorylation-regulated axonal dependent transport of syntaxin 1 is mediated by a Kinesin-1 adapter

Chua

Butkevich

Worseck

et al. 2012

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

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“…This is based on the localization of tubal carcinomas to the fimbria (17), the association of many peritoneal and ovarian serous carcinomas with the fimbriated end (61) and expression of (mutant) p53 in a secretory cell of the fimbria (16). Dynein motor complex involvement in retrograde transport should also be considered in the biology of LMP tumors as Dynein retrograde transport has been linked to MAPK [stress-activated protein kinase/c-Jun NH 2 kinase (SAPK/JNK)] signaling (62,63). Although a number of key molecules implicated in control of this vesicle transport chain, including DLK1 and MAP3K5, seem to be up-regulated in LMP tumors (versus highgrade invasive), the pathway has been mostly studied in the context of neuronal transport and axonal damage repair (64,65), and its relation to tumor pathobiology has not been explored.…”

Section: Discussionmentioning

confidence: 99%

Mutation of ERBB2 Provides a Novel Alternative Mechanism for the Ubiquitous Activation of RAS-MAPK in Ovarian Serous Low Malignant Potential Tumors

Anglesio

Arnold²,

George³

et al. 2008

Molecular Cancer Research

111

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Approximately, 10% to 15% of serous ovarian tumors fall into the category designated as tumors of low malignant potential (LMP). Like their invasive counterparts, LMP tumors may be associated with extraovarian disease, for example, in the peritoneal cavity and regional lymph nodes. However, unlike typical invasive carcinomas, patients generally have a favorable prognosis. The mutational profile also differs markedly from that seen in most serous carcinomas. Typically, LMP tumors are associated with KRAS and BRAF mutations. Interrogation of expression profiles in serous LMP tumors suggested overall redundancy of RAS-MAPK pathway mutations and a distinct mechanism of oncogenesis compared with high-grade ovarian carcinomas. Our findings indicate that activating mutation of the RAS-MAPK pathway in serous LMP may be present in >70% of cases compared with f12.5% in serous ovarian carcinomas. In addition to mutations of KRAS (18%) and BRAF (48%) mutations, ERBB2

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“…JNKs show constitutively high activity within neurons and phosphorylate various cytoskeletal proteins involved in axon extension, including MAP1B, MAP2, tau, and SCG10, among others (Kyriakis and Avruch 1990;Otto et al 2000;Neidhart et al 2001;Tararuk et al 2006;Yamauchi et al 2006;Ciani and Salinas 2007). Axonal transport is modulated by JNK, and it has been proposed that JNK triggers the release of cargoes, such as tubulin, from kinesin complexes (Stagi et al 2006;Horiuchi et al 2007). It is clear that the repertoire of JNK substrates is well-suited to mediate many aspects of axonal development.…”

Section: Jnk Signaling and Axon Elongationmentioning

confidence: 99%

Initiating and Growing an Axon

Polleux¹,

Snider²

2010

Cold Spring Harbor Perspectives in Biology

161

127

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The ability of neurons to form a single axon and multiple dendrites underlies the directional flow of information transfer in the central nervous system. Dendrites and axons are molecularly and functionally distinct domains. Dendrites integrate synaptic inputs, triggering the generation of action potentials at the level of the soma. Action potentials then propagate along the axon, which makes presynaptic contacts onto target cells. This article reviews what is known about the cellular and molecular mechanisms underlying the ability of neurons to initiate and extend a single axon during development. Remarkably, neurons can polarize to form a single axon, multiple dendrites, and later establish functional synaptic contacts in reductionist in vitro conditions. This approach became, and remains, the dominant model to study axon initiation and growth and has yielded the identification of many molecules that regulate axon formation in vitro (Dotti et al. 1988). At present, only a few of the genes identified using in vitro approaches have been shown to be required for axon initiation and outgrowth in vivo. In vitro, axon initiation and elongation are largely intrinsic properties of neurons that are established in the absence of relevant extracellular cues. However, the importance of extracellular cues to axon initiation and outgrowth in vivo is emerging as a major theme in neural development (Barnes and Polleux 2009). In this article, we focus our attention on the extracellular cues and signaling pathways required in vivo for axon initiation and axon extension.

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Control of a Kinesin-Cargo Linkage Mechanism by JNK Pathway Kinases

Cited by 145 publications

References 31 publications

Phosphorylation-regulated axonal dependent transport of syntaxin 1 is mediated by a Kinesin-1 adapter

Phosphorylation-regulated axonal dependent transport of syntaxin 1 is mediated by a Kinesin-1 adapter

Mutation of ERBB2 Provides a Novel Alternative Mechanism for the Ubiquitous Activation of RAS-MAPK in Ovarian Serous Low Malignant Potential Tumors

Initiating and Growing an Axon

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