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)

Kinesins are a large superfamily of microtubule motors that mediate specific motile processes. In a previous study, we identified 11 kinesin family members in the retina and retinal pigment epithelium (RPE) of the striped bass, Morone saxatilus. We have now identified, cloned, and sequenced the human homologue (KIFC3) of the most abundantly expressed retinal kinesin from that study, the C-terminal kinesin FKIF2. An antibody raised against an FKIF2 peptide cross-reacted with an approximately 80-kDa protein in human retina, RPE, kidney, and lung. Since microtubule-dependent processes are critical to the function and morphogenesis of the photoreceptors and RPE, the abundantly expressed KIFC3 was considered to be a potential candidate gene for causing human retinal degeneration. Chromosomal localization of the KIFC3 gene revealed that it maps to chromosome 16q13-q21, within the critical region for a Bardet-Biedl syndrome locus (BBS2). Bardet-Biedl syndrome is a genetically heterogeneous, autosomal recessive disorder characterized by retinal dystrophy, polydactyly, obesity, hypogonadism, renal abnormalities, and mental retardation. The chromosomal localization and expression pattern of KIFC3 suggest that it may be an excellent candidate for families linked to BBS2.
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PMID:Cloning of a novel C-terminal kinesin (KIFC3) that maps to human chromosome 16q13-q21 and thus is a candidate gene for Bardet-Biedl syndrome. 978 90

Many forms of intracellular transport are mediated by microtubule-dependent motors of the kinesin superfamily (KIFs). To identify kinesins expressed in human retina and RPE, we used degenerate primer RT-PCR to amplify a approximately 440 bp kinesin motor domain fragment from human retinal and RPE messenger RNAs. Four distinct kinesins were detected: one C-kinesin (HsKIFC3); one kinesin from the unc104/KIF1 family [HsKIF1A]; and the ubiquitous and neuronal forms of conventional kinesin heavy chain [HsuKHC and HsnKHC]. The C-kinesin HsKIFC3 comprised 33.3% of the retinal clones and was 60% identical to FKIF2, the most abundant kinesin detected in a previous screen of fish retina and 95% identical to a fragment of MmKifC3 recently amplified from mouse brain. Elsewhere we have reported the sequence of HsKIFC3 and shown that it maps to the same locus on chromosome 16q13-q21 as Bardet-Biedl syndrome Type II, a hereditary retinal degeneration. We describe here the kinesin PCR screen of human retina and RPE and examine the tissue and subcellular distribution of KIFC3 in both fish and human retina using an antibody raised against a peptide conserved between FKIF2 and HsKIFC3. This peptide antibody identified a single approximately 80 kDa band in Western blots of fish and human retina and RPE. In both fish and human retina this antibody strongly labeled photoreceptor terminals in the outer plexiform layer, suggesting that FKIF2/KIFC3 may play some role in the photoreceptor synapse.
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PMID:Characterization of a novel C-kinesin (KIFC3) abundantly expressed in vertebrate retina and RPE. 1037 49

Necdin and Magel2 are related proteins inactivated in Prader-Willi syndrome (PWS), a sporadic chromosomal deletion disorder. We demonstrate that necdin and Magel2 bind to and prevent proteasomal degradation of Fez1, a fasciculation and elongation protein implicated in axonal outgrowth and kinesin-mediated transport, and also bind to the Bardet-Biedl syndrome (BBS) protein BBS4 in co-transfected cells. The interactions among necdin, Magel2, Fez1 and BBS4 occur at or near centrosomes. Centrosomal or pericentriolar dysfunction has previously been implicated in BBS and may also be important in the features of PWS that overlap with BBS, such as learning disabilities, hypogonadism and obesity. Morphological abnormalities in axonal outgrowth and fasciculation manifest in several regions of the nervous system in necdin null mouse embryos, including axons of sympathetic, retinal ganglion cell, serotonergic and catecholaminergic neurons. These data demonstrate that necdin mediates intracellular processes essential for neurite outgrowth and that loss of necdin impinges on axonal outgrowth. We further suggest that loss of necdin contributes to the neurological phenotype of PWS, and raise the possibility that co-deletion of necdin and the related protein Magel2 may explain the lack of single gene mutations in PWS.
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PMID:Essential role for the Prader-Willi syndrome protein necdin in axonal outgrowth. 1564 43

Cilia have diverse roles in motility and sensory reception, and defects in cilia function contribute to ciliary diseases such as Bardet-Biedl syndrome (BBS). Intraflagellar transport (IFT) motors assemble and maintain cilia by transporting ciliary precursors, bound to protein complexes called IFT particles, from the base of the cilium to their site of incorporation at the distal tip. In Caenorhabditis elegans, this is accomplished by two IFT motors, kinesin-II and osmotic avoidance defective (OSM)-3 kinesin, which cooperate to form two sequential anterograde IFT pathways that build distinct parts of cilia. By observing the movement of fluorescent IFT motors and IFT particles along the cilia of numerous ciliary mutants, we identified three genes whose protein products mediate the functional coordination of these motors. The BBS proteins BBS-7 and BBS-8 are required to stabilize complexes of IFT particles containing both of the IFT motors, because IFT particles in bbs-7 and bbs-8 mutants break down into two subcomplexes, IFT-A and IFT-B, which are moved separately by kinesin-II and OSM-3 kinesin, respectively. A conserved ciliary protein, DYF-1, is specifically required for OSM-3 kinesin to dock onto and move IFT particles, because OSM-3 kinesin is inactive and intact IFT particles are moved by kinesin-II alone in dyf-1 mutants. These findings implicate BBS ciliary disease proteins and an OSM-3 kinesin activator in the formation of two IFT pathways that build functional cilia.
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PMID:Functional coordination of intraflagellar transport motors. 1604 94

The assembly and function of cilia on Caenorhabditis elegans neurons depends on the action of two kinesin-2 motors, heterotrimeric kinesin-II and homodimeric OSM-3-kinesin, which cooperate to move the same intraflagellar transport (IFT) particles along microtubule (MT) doublets. Using competitive in vitro MT gliding assays, we show that purified kinesin-II and OSM-3 cooperate to generate movement similar to that seen along the cilium in the absence of any additional regulatory factors. Quantitative modeling suggests that this could reflect an alternating action mechanism, in which the motors take turns to move along MTs, or a mechanical competition, in which the motors function in a concerted fashion to move along MTs with the slow motor exerting drag on the fast motor and vice versa. In vivo transport assays performed in Bardet-Biedl syndrome (BBS) protein and IFT motor mutants favor a mechanical competition model for motor coordination in which the IFT motors exert a BBS protein-dependent tension on IFT particles, which controls the IFT pathway that builds the cilium foundation.
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PMID:Mechanism of transport of IFT particles in C. elegans cilia by the concerted action of kinesin-II and OSM-3 motors. 1700 Aug 80

Although human congenital cerebellar malformations are common, their molecular and developmental basis is still poorly understood. Recently, cilia-related gene deficiencies have been implicated in several congenital disorders that exhibit cerebellar abnormalities such as Joubert syndrome, Meckel-Gruber syndrome, Bardet-Biedl syndrome, and Orofaciodigital syndrome. The association of cilia gene mutations with these syndromes suggests that cilia may be important for cerebellar development, but the nature of cilia involvement has not been elucidated. To assess the importance of cilia-related proteins during cerebellar development, we studied the effects of CNS-specific inactivation of two mouse genes whose protein products are critical for cilia formation and maintenance, IFT88, (also known as polaris or Tg737), which encodes intraflagellar transport 88 homolog, and Kif3a, which encodes kinesin family member 3a. We showed that loss of either of these genes caused severe cerebellar hypoplasia and foliation abnormalities, primarily attributable to a failure of expansion of the neonatal granule cell progenitor population. In addition, granule cell progenitor proliferation was sensitive to partial loss of IFT function in a hypomorphic mutant of IFT88 (IFT88(orpk)), an effect that was modified by genetic background. IFT88 and Kif3a were not required for the specification and differentiation of most other cerebellar cell types, including Purkinje cells. Together, our observations constitute the first demonstration that cilia proteins are essential for normal cerebellar development and suggest that granule cell proliferation defects may be central to the cerebellar pathology in human cilia-related disorders.
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PMID:Cilia proteins control cerebellar morphogenesis by promoting expansion of the granule progenitor pool. 1780 38

MIP-T3 is a human protein found previously to associate with microtubules and the kinesin-interacting neuronal protein DISC1 (Disrupted-in-Schizophrenia 1), but whose cellular function(s) remains unknown. Here we demonstrate that the C. elegans MIP-T3 ortholog DYF-11 is an intraflagellar transport (IFT) protein that plays a critical role in assembling functional kinesin motor-IFT particle complexes. We have cloned a loss of function dyf-11 mutant in which several key components of the IFT machinery, including Kinesin-II, as well as IFT subcomplex A and B proteins, fail to enter ciliary axonemes and/or mislocalize, resulting in compromised ciliary structures and sensory functions, and abnormal lipid accumulation. Analyses in different mutant backgrounds further suggest that DYF-11 functions as a novel component of IFT subcomplex B. Consistent with an evolutionarily conserved cilia-associated role, mammalian MIP-T3 localizes to basal bodies and cilia, and zebrafish mipt3 functions synergistically with the Bardet-Biedl syndrome protein Bbs4 to ensure proper gastrulation, a key cilium- and basal body-dependent developmental process. Our findings therefore implicate MIP-T3 in a previously unknown but critical role in cilium biogenesis and further highlight the emerging role of this organelle in vertebrate development.
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PMID:An essential role for DYF-11/MIP-T3 in assembling functional intraflagellar transport complexes. 1836 62

Nonmotile primary cilia are sensory organelles composed of a microtubular axoneme and a surrounding membrane sheath that houses signaling molecules. Optimal cellular function requires the precise regulation of axoneme assembly, membrane biogenesis, and signaling protein targeting and localization via as yet poorly understood mechanisms. Here, we show that sensory signaling is required to maintain the architecture of the specialized AWB olfactory neuron cilia in C. elegans. Decreased sensory signaling results in alteration of axoneme length and expansion of a membraneous structure, thereby altering the topological distribution of a subset of ciliary transmembrane signaling molecules. Signaling-regulated alteration of ciliary structures can be bypassed by modulation of intracellular cGMP or calcium levels and requires kinesin-II-driven intraflagellar transport (IFT), as well as BBS- and RAB8-related proteins. Our results suggest that compensatory mechanisms in response to altered levels of sensory activity modulate AWB cilia architecture, revealing remarkable plasticity in the regulation of cilia structure.
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PMID:Sensory signaling-dependent remodeling of olfactory cilia architecture in C. elegans. 1847 43

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