Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.6.4.4 (kinesin)
5,033 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The nerve axon is a good model system for studying the molecular mechanism of organelle transport in cells. Recently, the new kinesin superfamily proteins (KIFs) have been identified as candidate motor proteins involved in organelle transport. Among them KIF1A, a murine homologue of unc-104 gene of Caenorhabditis elegans, is a unique monomeric neuron- specific microtubule plus end-directed motor and has been proposed as a transporter of synaptic vesicle precursors (Okada, Y., H. Yamazaki, Y. Sekine-Aizawa, and N. Hirokawa. 1995. Cell. 81:769-780). To elucidate the function of KIF1A in vivo, we disrupted the KIF1A gene in mice. KIF1A mutants died mostly within a day after birth showing motor and sensory disturbances. In the nervous systems of these mutants, the transport of synaptic vesicle precursors showed a specific and significant decrease. Consequently, synaptic vesicle density decreased dramatically, and clusters of clear small vesicles accumulated in the cell bodies. Furthermore, marked neuronal degeneration and death occurred both in KIF1A mutant mice and in cultures of mutant neurons. The neuronal death in cultures was blocked by coculture with wild-type neurons or exposure to a low concentration of glutamate. These results in cultures suggested that the mutant neurons might not sufficiently receive afferent stimulation, such as neuronal contacts or neurotransmission, resulting in cell death. Thus, our results demonstrate that KIF1A transports a synaptic vesicle precursor and that KIF1A-mediated axonal transport plays a critical role in viability, maintenance, and function of neurons, particularly mature neurons.
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PMID:Defect in synaptic vesicle precursor transport and neuronal cell death in KIF1A motor protein-deficient mice. 954 21

The kinesin superfamily proteins (KIFs) play essential roles in receptor transportation along the microtubules. KIF17 transports the N-methyl-d-aspartate receptor NR2B subunit in vitro, but its role in vivo is unknown. To clarify this role, we generated transgenic mice overexpressing KIF17 tagged with GFP. The KIF17 transgenic mice exhibited enhanced learning and memory in a series of behavioral tasks, up-regulated NR2B expression with the potential involvement of a transcriptional factor, the cAMP-dependent response element-binding protein, and increased phosphorylation of the cAMP-dependent response element-binding protein. Our results suggest that the motor protein KIF17 contributes to neuronal events required for learning and memory by trafficking fundamental N-methyl-d-aspartate-type glutamate receptors.
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PMID:Overexpression of motor protein KIF17 enhances spatial and working memory in transgenic mice. 1239 Dec 94

Liprin-alpha/SYD-2 is a multimodular scaffolding protein important for presynaptic differentiation and postsynaptic targeting of alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid glutamate receptors. However, the molecular mechanisms underlying these functions remain largely unknown. Here we report that liprin-alpha interacts with the neuron-specific kinesin motor KIF1A. KIF1A colocalizes with liprin-alpha in various subcellular regions of neurons. KIF1A coaccumulates with liprin-alpha in ligated sciatic nerves. KIF1A cofractionates and coimmunopreciptates with liprin-alpha and various liprin-alpha-associated membrane, signaling, and scaffolding proteins including alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid receptors, GRIP/ABP, RIM, GIT1, and beta PIX. These results suggest that liprin-alpha functions as a KIF1A receptor, linking KIF1A to various liprin-alpha-associated proteins for their transport in neurons.
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PMID:Association of the kinesin motor KIF1A with the multimodular protein liprin-alpha. 1252 3

Human PPFIA1 (also known as LIP.1 or Liprin alpha1) gene, located within CCND1-FGF4-EMS1 amplicon at human chromosome 11q13.3, encodes KIF1A-binding protein, which is implicated in trafficking of LAR subfamily PTPases and AMPA-type glutamate receptors. Human PPFIA4 (AF034801) and rat Ppfia4 (AY057064) are 5'-truncated partial cDNAs, and the complete coding sequence of PPFIA4 ortholog of any species remained to be identified. Here, we determined the complete coding sequence of human PPFIA4 gene by using bioinformatics. Exons 1-12 of PPFIA4 gene were located within human genome sequence AC096632.3, while exons 11-29 within AL451082.6. PPFIA4-MYOG locus (human chromosome 1q32.1) was paralogous to PPFIA2-LIN7A-MYF5-MYF6 locus (12q21.31), which was also paralogous to PPFIA3-LIN7B locus (19q13.41). PPFIA4 (1186 aa) showed 70.9%, 67.1%, and 61.8% total-amino-acid identity with PPFIA2, PPFIA1, and PPFIA3, respectively. PPFIA family members consist of PFIH1, PFIH2, PFIH3, PFIH4 domains and three SAM (Sterile alpha motif) domains. C-terminal binding domain for GRIP proteins (VRTYSC motif) was present in PPFIA1, PPFIA2 and PPFIA3, but not in PPFIA4. Bipartite nuclear localization signal was included within PFIH4 domain. PFIH2 domain was identical to ERM or Smc domain. The region spanning PFIH2-PFIH3 domains is the binding domain for KIF1A. The region spanning SAM1-SAM3 domains is the binding domain for LAR subfamily PTPases and PPFIBP (Liprin beta) family proteins. This is the first report on comprehensive characterization of PPFIA4 belonging to the PPFIA family of kinesin-cargo linkers.
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PMID:Identification and characterization of human PPFIA4 gene in silico. 1461 82

Several human neurodegenerative diseases are associated with abnormal accumulations of aggregated tau proteins and glial degeneration in astrocytes, but the mechanism whereby tau proteins cause astrocytic degeneration is unclear. Here, we analyzed the biological consequences of overexpressing the longest human tau isoform in primary cultures of rat astrocytes using adenoviral-mediated gene transfer. Significantly, we found specific decreases in stable detyrosinated [glutamate (Glu)] microtubules (MTs) with concomitant increases in tubulin biosynthesis and the accumulation of acetylated, tyrosinated, alpha- and beta-tubulin. The consequences of this selective reduction in stable Glu-MTs included contemporaneous decreases in kinesin levels, collapse of the intermediate filament network, progressive disruption of kinesin-dependent trafficking of organelles, fragmentation of the Golgi apparatus that culminated in atrophy, and non-apoptotic death of astrocytes. These results suggest that reduced stable Glu-MTs is a primary consequence of tau accumulation that initiates mechanisms underlying astrocyte dysfunction and death in human neurodegenerative glial tauopathies.
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PMID:Reduction of detyrosinated microtubules and Golgi fragmentation are linked to tau-induced degeneration in astrocytes. 1462 51

Gamma-aminobutyric acid(A) receptor-interacting factor (GRIF-1) is a 913-amino acid protein proposed to function as a GABA(A) receptor beta(2) subunit-interacting, trafficking protein. GRIF-1 shares approximately 44% amino acid sequence identity with O-linked N-acetylglucosamine transferase interacting protein 106, OIP106. Both proteins contain predicted coiled-coil domains and probably constitute a novel gene family. The Drosophila orthologue of this family of proteins may be Milton. Milton shares approximately 44% amino acid homology with GRIF-1. Milton is proposed to function in kinesin-mediated transport of mitochondria to nerve terminals. We report here that GRIF-1 and OIP106 also associate with kinesin and mitochondria. Following expression in human embryonic kidney 293 cells, both GRIF-1 and OIP106 were shown by co-immunoprecipitation to be specifically associated with an endogenous kinesin heavy chain species of 115 kDa and exogenous KIF5C. Association of GRIF-1 with kinesin was also evident in native brain and heart tissue. In the brain, anti-GRIF-1-(8-633) antibodies specifically co-immunoprecipitated two kinesin-immunoreactive species with molecular masses of 118 and 115 kDa, and in the heart, one kinesin-immunoreactive species, 115 kDa, was immunoprecipitated. Further studies revealed that GRIF-1 was predominantly associated with KIF5A in the brain and with KIF5B in both the heart and in HEK 293 cells. Yeast two-hybrid interaction assays and immunoprecipitations showed that GRIF-1 associated directly with KIF5C with the GRIF-1/KIF5C interaction domain localized to GRIF-1-(124-283). These results further support a role for GRIF-1 and OIP106 in protein and/or organelle transport in excitable cells in a manner analogous to glutamate receptor-interacting-protein 1, in the motor-dependent transport of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate glutamate excitatory neurotransmitter receptors to dendrites.
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PMID:GRIF-1 and OIP106, members of a novel gene family of coiled-coil domain proteins: association in vivo and in vitro with kinesin. 1564 24

Defective axonal transport has been proposed as an underlying mechanism that may give rise to neurodegeneration. We investigated the effect of phosphorylation on the axonal transport of tau, a neuronal protein that stabilizes microtubules and is hyperphosphorylated and mislocalized in Alzheimer's disease. We report here that specific inhibition of glycogen synthase kinase-3 (GSK-3) reduces tau phosphorylation and significantly decreases the overall rate of axonal transport of tau in rat cortical neurons. Tau mutants, with serine/threonine targets of GSK-3 mutated to glutamate to mimic a permanent state of phosphorylation, were transported at a significantly increased rate compared to wild-type tau. Conversely, tau mutants, in which alanine replaced serine/threonine to mimic permanent dephosphorylation, were transported at a decreased rate compared to wild-type tau. We also found that tau interacts with the light chain of kinesin-1 and that this is dependent on the phosphorylation state of tau. Tau phosphorylation by GSK-3 increased binding, and dephosphorylated tau exhibited a reduced association with kinesin-1. We conclude that GSK-3 phosphorylation of tau modulates its axonal transport by regulating binding to kinesin-1. Hyperphosphorylated tau in Alzheimer's disease appearing first in distal portions of axons may result from aberrant axonal transport of phosphorylated tau reported here.
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PMID:Phosphorylation of tau regulates its axonal transport by controlling its binding to kinesin. 1851 49

It was earlier shown that expression of kinesin superfamily-associated protein 3 (KAP3), involved in the neuronal anterograde, microtubule-dependent transport of membrane organelles, increases in the hypothalamus of female rats during the juvenile phase of sexual development. KAP3 mRNA is abundant in the hypothalamus, suggesting that it might be expressed in broadly disseminated neuronal systems controlling neuroendocrine function. The present study identifies one of these systems and provides evidence for an involvement of KAP3 in the excitatory control of female puberty. In situ hybridization and immunohistofluorescence studies revealed that the KAP3 gene is expressed in glutamatergic neurons but not in GABAergic or GnRH neurons. Hypothalamic KAP3 mRNA levels increase during the juvenile period of female prepubertal development, remaining elevated throughout puberty. These changes appear to be, at least in part, estradiol dependent because ovariectomy decreases and estradiol increases KAP3 mRNA abundance. Lowering hypothalamic KAP3 protein levels via intraventricular administration of an antisense oligodeoxynucleotide resulted in reduced release of both glutamate and GnRH from the median eminence and delayed the onset of puberty. The median eminence content of vesicular glutamate transporter 2, a glutamate neuron-selective synaptic protein, and synaptophysin, a synaptic vesicle marker, were also reduced, suggesting that the loss of KAP3 diminishes the anterograde transport of these proteins. Altogether, these results support the view that decreased KAP3 synthesis diminishes GnRH output and delays female sexual development by compromising hypothalamic release of glutamate.
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PMID:Kinesin superfamily-associated protein 3 is preferentially expressed in glutamatergic neurons and contributes to the excitatory control of female puberty. 1870 27

Histone deacetylase 1 (HDAC1) is a nuclear enzyme involved in transcriptional repression. We detected cytosolic HDAC1 in damaged axons in brains of humans with multiple sclerosis and of mice with cuprizone-induced demyelination, in ex vivo models of demyelination and in cultured neurons exposed to glutamate and tumor necrosis factor-alpha. Nuclear export of HDAC1 was mediated by the interaction with the nuclear receptor CRM-1 and led to impaired mitochondrial transport. The formation of complexes between exported HDAC1 and members of the kinesin family of motor proteins hindered the interaction with cargo molecules, thereby inhibiting mitochondrial movement and inducing localized beading. This effect was prevented by inhibiting HDAC1 nuclear export with leptomycin B, treating neurons with pharmacological inhibitors of HDAC activity or silencing HDAC1 but not other HDAC isoforms. Together these data identify nuclear export of HDAC1 as a critical event for impaired mitochondrial transport in damaged neurons.
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PMID:HDAC1 nuclear export induced by pathological conditions is essential for the onset of axonal damage. 2010 3

In the retina, dopamine fulfills a crucial role in neural adaptation to photopic illumination, but the pathway that carries cone signals to the dopaminergic amacrine (DA) cells was controversial. We identified the site of ON-cone bipolar input onto DA cells in transgenic mice in which both types of catecholaminergic amacrine (CA) cells were labeled with green fluorescent protein or human placental alkaline phosphatase (PLAP). In confocal Z series of retinal whole mounts stained with antibodies to tyrosine hydroxylase (TH), DA cells gave rise to varicose processes that descended obliquely through the scleral half of the inner plexiform layer (IPL) and formed a loose, tangential plexus in the middle of this layer. Comparison with the distribution of the dendrites of type 2 CA cells and examination of neurobiotin-injected DA cells proved that their vitreal processes were situated in stratum S3 of the IPL. Electron microscope demonstration of PLAP activity showed that bipolar cell endings in S3 established ribbon synapses onto a postsynaptic dyad in which one or both processes were labeled by a precipitate of lead phosphate and therefore belonged to DA cells. In places, the postsynaptic DA cell processes returned a reciprocal synapse onto the bipolar endings. Confocal images of sections stained with antibodies to TH, kinesin Kif3a, which labels synaptic ribbons, and glutamate or GABA(A) receptors, confirmed that ribbon-containing endings made glutamatergic synapses onto DA cells processes in S3 and received from them GABAergic synapses. The presynaptic ON-bipolar cells most likely belonged to the CB3 (type 5) variety.
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PMID:Synaptic input of ON-bipolar cells onto the dopaminergic neurons of the mouse retina. 2039 57


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