A kinesin-dependent movement of particles in the flagella of Chlamydomonas reinhardtii called intraflagellar transport (IFT) has been described. When IFT is inhibited by inactivation of a kinesin, FLA10, in the temperature-sensitive mutant, fla10, existing flagella resorb and new flagella cannot be assembled. The IFT-associated FLA10 protein is a subunit of a heterotrimeric kinesin. IFT particles are composed of 15 polypeptides comprising two large complexes. The FLA10 kinesin-II and IFT particle polypeptides, in addition to being found in flagella, are highly concentrated around the flagellar basal bodies. Mutations affecting homologs of two of the IFT particle polypeptides in Caenorhabditis elegans result in defects in the sensory cilia located on the dendritic processes of sensory neurons. A Chlamydomonas mutant (fla14) has has been described in which only the retrograde transport of IFT particles is disrupted, resulting in assembly-defective flagella filled with an excess of IFT particles. This microtubule- dependent transport process, IFT, defined by mutants in both the anterograde (fla10) and retrograde (fla14) transport of isolable particles, is probably essential for the maintenance and assembly of all eukaryotic motile flagella and nonmotile sensory cilia (Cole, 1998).
Intraflagellar transport (IFT) is the bidirectional movement of multisubunit protein particles along axonemal microtubules and is required for assembly and maintenance of eukaryotic flagella and cilia. One posited role of IFT is to transport flagellar precursors to the flagellar tip for assembly. This study examines radial spokes, axonemal subunits consisting of 22 polypeptides, as potential cargo for IFT. Radial spokes were found to be partially assembled in the cell body, before being transported to the flagellar tip by anterograde IFT. Fully assembled radial spokes, detached from axonemal microtubules during flagellar breakdown or turnover, are removed from flagella by retrograde IFT. Interactions between IFT particles, motors, radial spokes, and other axonemal proteins were verified by coimmunoprecipitation of these proteins from the soluble fraction of Chlamydomonas flagella. These studies indicate that one of the main roles of IFT in flagellar assembly and maintenance is to transport axonemal proteins in and out of the flagellum (Qin, 2004).
Intraflagellar transport (IFT), the bidirectional movement of particles along flagella, is essential for flagellar assembly. The motor for retrograde IFT in Chlamydomonas is cytoplasmic dynein 1b, which contains the dynein heavy chain DHC1b and the light intermediate chain (LIC) D1bLIC. To investigate a possible role for the LIC in IFT, a d1blic mutant was generated. DHC1b is reduced in the mutant, indicating that D1bLIC is important for stabilizing dynein 1b. The mutant has variable length flagella that accumulate IFT-particle proteins, indicative of a defect in retrograde IFT. Interestingly, the remaining DHC1b is normally distributed in the mutant flagella, strongly suggesting that the defect is in binding of cargo to the retrograde motor rather than in motor activity per se. Cell growth and Golgi apparatus localization and morphology are normal in the mutant, indicating that D1bLIC is involved mainly in retrograde IFT. Like mammalian LICs, D1bLIC has a phosphate-binding domain (P-loop) at its N-terminus. To investigate the function of this conserved domain, d1blic mutant cells were transformed with constructs designed to express D1bLIC proteins with mutated P-loops. The constructs rescued the mutant cells to a wild-type phenotype, indicating that the function of D1bLIC in IFT is independent of its P-loop (Hou, 2004).
Chemosensation in the nervous system of the nematode C. elegans depends on sensory cilia, whose assembly and maintenance requires the transport of components such as axonemal proteins and signal transduction machinery to their site of incorporation into ciliary structures. Members of the heteromeric kinesin family of microtubule motors are prime candidates for playing key roles in these transport events. The molecular characterization and partial purification is described of two heteromeric kinesin complexes from C. elegans, heterotrimeric CeKinesin-II and dimeric CeOsm-3. Transgenic worms expressing green fluorescent protein driven by endogenous heteromeric kinesin promoters reveal that both CeKinesin-II and CeOsm-3 are expressed in amphid, inner labial, and phasmid chemosensory neurons. Additionally, immunolocalization experiments on fixed worms show an intense concentration of CeKinesin-II and CeOsm-3 polypeptides in the ciliated endings of these chemosensory neurons and a punctate localization pattern in the corresponding cell bodies and dendrites. These results, together with the phenotypes of known mutants in the pathway of sensory ciliary assembly, suggest that CeKinesin-II and CeOsm-3 drive the transport of ciliary components required for sequential steps in the assembly of chemosensory cilia (Signor, 1999).
Cilia are present on cells of many eukaryotic organisms and recent data in the mouse suggest that ciliary defects can cause severe developmental abnormalities and disease. Studies across eukaryotic systems indicate that cilia are constructed and maintained through a highly conserved process termed intraflagellar transport (IFT), for which many of the proteins involved have yet to be identified. IFT describes the movement of large protein particles consisting of an A and a B complex along the cilia axoneme in anterograde and retrograde directions. A novel C. elegans gene, F59C6.7/9, is described that is required for cilia assembly and whose function is disrupted in che-13 ciliogenic mutants. As has been shown for all IFT complex B genes identified to date, expression of che-13 (F59C6.7/9) is regulated by the RFX-type transcription factor DAF-19, suggesting a conserved transcriptional pathway in ciliogenesis. Fluorescent-tagged CHE-13 protein concentrates at the base of cilia and moves along the axoneme as expected for an IFT protein. Furthermore, loss of che-13 differentially affects the localization of two known IFT complex B proteins, OSM-5 and OSM-6, implying that CHE-13 functions as part of this complex. Overall, these data confirm that CHE-13 is an IFT protein and further that the IFT particle assembles in an ordered process through specific protein-protein interactions (Haycraft, 2003).
Bardet-Biedl syndrome (BBS) is a genetically heterogeneous developmental disorder whose molecular basis is largely unknown. Mutations in the Caenorhabditis elegans bbs-7 and bbs-8 genes cause structural and functional defects in cilia. C. elegans BBS proteins localize predominantly at the base of cilia, and like proteins involved in intraflagellar transport (IFT), a process necessary for cilia biogenesis and maintenance, these proteins move bidirectionally along the ciliary axoneme. Importantly, BBS-7 and BBS-8 are required for the normal localization/motility of the IFT proteins OSM-5/Polaris and CHE-11, and to a notably lesser extent, CHE-2. It is proposed that BBS proteins play important, selective roles in the assembly and/or function of IFT particle components. These findings also suggest that some of the cardinal and secondary symptoms of BBS, such as obesity, diabetes, cardiomyopathy, and learning defects may result from cilia dysfunction (Blacque, 2004).
Cilia and flagella are widespread eukaryotic subcellular components that are conserved from green algae to mammals. In different organisms they function in cell motility, movement of extracellular fluids and sensory reception. While the function and structural description of cilia and flagella are well established, there are many questions that remain unanswered. In particular, very little is known about the developmental mechanisms by which cilia are generated and shaped and how their components are assembled into functional machineries. To find genes involved in cilia development a promoter motif, the X-box, which participates in the regulation of certain ciliary genes in the nematode Caenorhabditis elegans, were used as a search tool. By using a genome search approach for X-box promoter motif-containing genes (xbx genes) a list of about 750 xbx genes (candidates) was generated. This list comprises some already known ciliary genes as well as new genes, many of which are hypothesized to be important for cilium structure and function. A C. elegans X-box consensus sequence was derived by in vivo expression analysis. It was found that xbx gene expression patterns are dependent on particular X-box nucleotide compositions and the distance from the respective gene start. A model is proposed where DAF-19, the RFX-type transcription factor binding to the X-box, is responsible for the development of a ciliary module in C. elegans, which includes genes for cilium structure, transport machinery, receptors and other factors (Efimenko, 2005).
Intraflagellar transport (IFT) underpins many of the important cellular roles of cilia and flagella in signaling and motility. The microtubule motors kinesin-2 and cytoplasmic dynein 1b drive IFT particles (protein complexes carrying ciliary component proteins) along the axoneme to facilitate the assembly and maintenance of cilia. IFT is regulated primarily by cargo loading onto the IFT particles, although evidence suggests that IFT particles also exhibit differential rates of movement. This study demonstrates that intraflagellar Ca(2+) elevations act to directly regulate the movement of IFT particles. IFT-driven movement of adherent flagella membrane glycoproteins in the model alga Chlamydomonas enables flagella-mediated gliding motility. This study finds that surface contact promotes the localized accumulation of IFT particles in Chlamydomonas flagella. Highly compartmentalized intraflagellar Ca(2+) elevations initiate retrograde transport of paused IFT particles to modulate their accumulation. Gliding motility induces mechanosensitive intraflagellar Ca(2+) elevations in trailing (dragging) flagella only, acting to specifically clear the accumulated microtubule motors from individual flagella and prevent a futile tug-of-war. These results demonstrate that compartmentalized intraciliary Ca(2+) signaling can regulate the movement of IFT particles and is therefore likely to play a central role in directing the movement and distribution of many ciliary proteins (Collingridge, 2013).
A transcriptional regulatory element was identified in the region between URE (upstream regulatory element) and DRE (DNA replication-related element) in the Drosophila PCNA gene promoter. This element plays an important role in promoter activity in living flies. A yeast one-hybrid screening using this element as a bait allowed isolation of a cDNA encoding a protein which binds to the element in vitro. Nucleotide sequence analyses reveal that the cDNA encodes a novel protein containing a characteristic DNA-binding domain conserved among the regulatory factor X (RFX) family proteins. This protein has been called Drosophila RFX2 (dRFX2) and this element dRFX2 site. To investigate the function of dRFX2 in vivo, the strategy was taken of analyzing the dominant negative effects against the endogenous dRFX2. Transgenic flies were established in which expression of HA-dRFX(202-480) carrying the amino acid sequences from 202 to 480 containing the RFX domain (DNA-binding domain) of dRFX2 was targeted to the cells in the eye imaginal discs. In the eye imaginal disc expressing the HA-dRFX(202-480), the G1-S transition and/or the progression of S phase were/was interrupted, and the ectopic apoptosis was induced, though photoreceptor cells differentiated normally. These results indicate that dRFX2 plays a role in G1-S transition and/or in progression of S phase (Otsuki, 2004).
Cilia play diverse roles in vertebrate and invertebrate sensory neurons. A mutation of the zebrafish oval (ovl) locus affects a component of the ciliary transport (IFT) mechanism, the IFT88 polypeptide. In mutant retina, cilia are generated but not maintained, producing the absence of photoreceptor outer segments. A loss of cilia also occurs in auditory hair cells and olfactory sensory neurons. In all three sense organs, cilia defects are followed by degeneration of sensory cells. Similar phenotypes are induced by the absence of the IFT complex B polypeptides, ift52 and ift57, but not by the loss of complex A protein, ift140. The degeneration of mutant photoreceptor cells is caused, at least partially, by the ectopic accumulation of opsins. These studies reveal an essential role for IFT genes in vertebrate sensory neurons and implicate the molecular components of intraflagellar transport in degenerative disorders of these cells (Tsujikawa, 2004).
Intraflagellar transport (IFT) is an evolutionarily conserved mechanism thought to be required for the assembly and maintenance of all eukaryotic cilia and flagella. Although IFT proteins are present in cells with sensory cilia, the organization of IFT protein complexes in those cells has not been analyzed. To determine whether the IFT complex is conserved in the sensory cilia of photo-receptors, protein interactions were investigated among four mammalian IFT proteins: IFT88/Polaris, IFT57/Hippi, IFT52/NGD5, and IFT20. IFT proteins extracted from bovine photoreceptor outer segments, a modified sensory cilium, co-fractionate at approximately 17 S, similar to IFT proteins extracted from mouse testis. Using antibodies to IFT88 and IFT57, it has been demonstrated that all four IFT proteins co-immunoprecipitate from lysates of mouse testis, kidney, and retina. This analysis was also extended to interactions outside of the IFT complex; an ATP-regulated co-immunoprecipitation of heterotrimeric kinesin II with the IFT complex was demonstrated. The internal architecture of the IFT complex was investigated using the yeast two-hybrid system. IFT20 exhibits a strong interaction with IFT57/Hippi and the kinesin II subunit, KIF3B. These data indicate that all four mammalian IFT proteins are part of a highly conserved complex in multiple ciliated cell types. Furthermore, IFT20 appears to bridge kinesin II with the IFT complex (Baker, 2003).
Intraflagellar transport (IFT) proteins were first identified as essential factors for the growth and maintenance of flagella in the single-celled alga Chlamydomonas reinhardtii. In a screen for embryonic patterning mutations induced by ethylnitrosourea, two mouse mutants, wimple (wim) and flexo (fxo) were identified that lack ventral neural cell types and show other phenotypes characteristic of defects in Sonic hedgehog signalling. Both mutations disrupt IFT proteins: the wim mutation is an allele of the previously uncharacterized mouse homolog of IFT172; and fxo is a new hypomorphic allele of polaris, the mouse homolog of IFT88. Genetic analysis shows that Wim, Polaris and the IFT motor protein Kif3a are required for Hedgehog signalling at a step downstream of Patched1 (the Hedgehog receptor) and upstream of direct targets of Hedgehog signalling. These data show that IFT machinery has an essential and vertebrate-specific role in Hedgehog signal transduction (Huangfu, 2003).
Bardet-Biedl syndrome (BBS) is a genetically heterogeneous disorder characterized primarily by retinal dystrophy, obesity, polydactyly, renal malformations and learning disabilities. Although five BBS genes have been cloned, the molecular basis of this syndrome remains elusive. BBS is probably caused by a defect at the basal body of ciliated cells. A new BBS gene, BBS8, has been cloned that encodes a protein with a prokaryotic domain, pilF, involved in pilus formation and twitching mobility. In one family, a homozygous null BBS8 mutation leads to BBS with randomization of left-right body axis symmetry, a known defect of the nodal cilium. BBS8 localizes specifically to ciliated structures, such as the connecting cilium of the retina and columnar epithelial cells in the lung. In cells, BBS8 localizes to centrosomes and basal bodies and interacts with PCM1, a protein probably involved in ciliogenesis. Finally, it is demonstrated that all available Caenorhabditis elegans BBS homologues are expressed exclusively in ciliated neurons, and contain regulatory elements for RFX, a transcription factor that modulates the expression of genes associated with ciliogenesis and intraflagellar transport (Ansley, 2003).
There are five members of the RFX family of transcription factors in mammals. While RFX5 plays a well-defined role in the immune system, the functions of RFX1 to RFX4 remain largely unknown. Mice with a deletion of the Rfx3 gene. RFX3-deficient mice exhibit frequent left-right (LR) asymmetry defects leading to a high rate of embryonic lethality and situs inversus in surviving adults. In vertebrates, specification of the LR body axis is controlled by monocilia in the embryonic node, and defects in nodal cilia consequently result in abnormal LR patterning. Consistent with this, Rfx3 is expressed in ciliated cells of the node and RFX3-deficient mice exhibit a pronounced defect in nodal cilia. In contrast to the case for wild-type embryos, for which a twofold increase in the length of nodal cilia during development is documented, the cilia are present but remain markedly stunted in mutant embryos. Finally, RFX3 is shown to regulate the expression of D2lic, the mouse orthologue of a Caenorhabditis elegans gene that is implicated in intraflagellar transport, a process required for the assembly and maintenance of cilia. In conclusion, RFX3 is essential for the differentiation of nodal monocilia and hence for LR body axis determination (Bonnafe, 2004).
Heterotrimeric kinesin-II is a plus end-directed microtubule (MT) motor protein consisting of distinct heterodimerized motor subunits associated with an accessory subunit. To probe the intracellular transport functions of kinesin-II, fertilized sea urchin eggs were microinjected with an anti-kinesin-II monoclonal antibody, and a dramatic inhibition of ciliogenesis was observed at the blastula stage characterized by the assembly of short, paralyzed, 9+0 ciliary axonemes that lack central pair MTs. Control embryos show no such defect and form swimming blastulae with normal, motile, 9+2 cilia that contain kinesin-II as detected by Western blotting. Injection of anti-kinesin-II into one blastomere of a two-cell embryo leads to the development of chimeric blastulae covered on one side with short, paralyzed cilia, and on the other with normal, beating cilia. A unimodal length distribution of short cilia is observed on anti-kinesin-II-injected embryos corresponding to the first mode of the trimodal distribution of ciliary lengths observed for control embryos. This short mode may represent a default ciliary assembly intermediate. It is hypothesized that kinesin-II functions during ciliogenesis to deliver ciliary components that are required for elongation of the assembly intermediate and for formation of stable central pair MTs. Thus, kinesin-II plays a critical role in embryonic development by supporting the maturation of nascent cilia to generate long motile organelles capable of producing the propulsive forces required for swimming and feeding (Morris, 1997).
Kinesin heavy chain and kinesin-related polypeptides (KRPs) comprise a family of motor proteins with diverse intracellular transport functions. Using pan-kinesin peptide antibodies that react with these proteins, a trimeric microtubule-binding and bundling protein, KRP (85/95) was purified from sea urchin eggs, comprising subunits of M(r) 115,000 (115K), 95K and 85K. Kinesin-related genes encode the 85K and 95K subunits, and the protein can be immunoprecipitated from cytosol as a trimeric complex using an 85K monoclonal antibody. Purified KRP(85/95) directs movements towards the 'plus' ends of microtubules. This protein is the first kinesin-related motor to be purified from its natural host cell in a native multimeric state (Cole, 1993)
The heterotrimeric kinesin-II holoenzyme purified from sea urchin (Strongylocentrotus purpuratus) eggs is assembled from two heterodimerized kinesin-related motor subunits of known sequence, together with a third, previously uncharacterized 115-kD subunit, SpKAP115. Using monospecific anti-SpKAP115 antibodies, the SpKAP115 subunit has been cloned and sequenced. The deduced sequence predicts a globular 95-kD non-motor 'accessory' polypeptide rich in alpha-helical segments that are generally not predicted to form coiled coils. Electron microscopy of individual rotary shadowed kinesin-II holoenzymes also suggests that SpKAP115 is globular, with a somewhat asymmetric morphology. Moreover, the SpKAP115 subunit lies at one end of the 51-nm-long kinesin-II complex, being separated from the two presumptive motor domains by an approximately 26-nm-long rod, in a manner similar to the light chains (KLCs) of kinesin itself. This indicates that SpKAP115 and the KLCs may have analogous functions, yet SpKAP115 does not display significant sequence similarity with the KLCs. The results show that kinesin and kinesin-II are assembled from highly divergent accessory polypeptides together with kinesin related motor subunits (KRPs) containing conserved motor domains linked to divergent tails. Despite the lack of sequence conservation outside the motor domains, there is striking conservation of the ultrastructure of the kinesin and kinesin-II holoenzymes (Wedaman, 1996).
KAP is the non-motor subunit of the heteromeric plus-end directed microtubule (MT) motor protein kinesin-II essential for normal cilia formation. Studies in Chlamydomonas have demonstrated that kinesin-II drives the anterograde intraflagellar transport (IFT) of protein complexes along ciliary axonemes. A green fluorescent protein (GFP) chimera of KAP, KAP-GFP, has been used to monitor movements of this kinesin-II subunit in cells of sea urchin blastulae where cilia are retracted and rebuilt with each mitosis. As expected if involved in IFT, KAP-GFP localized to apical cytoplasm, basal bodies, and cilia and became concentrated on basal bodies of newly forming cilia. Surprisingly, after ciliary retraction early in mitosis, KAP-GFP moved into nuclei before nuclear envelope breakdown, they were again present in nuclei after nuclear envelope reformation, and only decreased in nuclei as ciliogenesis reinitiated. Nuclear transport of KAP-GFP could be due to a putative nuclear localization signal and nuclear export signals identified in the sea urchin KAP primary sequence. These observations of a protein involved in IFT being imported into the nucleus after ciliary retraction and again after nuclear envelope reformation suggest KAP115 may serve as a signal to the nucleus to reinitiate cilia formation during sea urchin development (Morris, 2004).
KIF3A and KIF3B form a heterodimer that functions as a microtubule-based fast anterograde translocator of membranous organelles. This KIF3A/3B forms a complex with other associated polypeptides, named kinesin superfamily-associated protein 3 (KAP3). KAP3 protein has been purified by immunoprecipitation using anti-KIF3B antibody from mouse testis. Microsequencing was carried out, and the full-length KAP3 cDNA was cloned from a mouse brain cDNA library. Two isoforms of KAP3 exist [KAP3A (793 aa) and KAP3B (772 aa)], generated by alternative splicing in the carboxyl terminus region. Their amino acid sequences have no homology with those of any other known proteins, and prediction of their secondary structure indicates that almost the entire KAP3 molecule is alpha-helical. Recombinant KAP3 and KIF3A/3B was produced using a baculovirus-Sf9 expression system. A reconstruction study in Sf9 cells revealed that KAP3 is a globular protein that binds to the tail domain of KIF3A/3B. The immunolocalization pattern of KAP3 is similar to that of KIF3A/3B in nerve cells. KAP3 does not affect the motor activity of KIF3A/3B. KAP3 is associated with a membrane-bound form of KIF3A/3B in a fractional immunoprecipitation experiment, and since the KIF3 complex was found to bind to membranous organelles in an EM study, KAP3 may regulate membrane binding of the KIF3 complex (Yamazaki, 1996).
SMAP (Smg GDS-associated protein; Smg GDS: small G protein GDP dissociation stimulator) has been isolated as a novel Smg GDS-associated protein, which has Armadillo repeats and is phosphorylated by Src tyrosine kinase. SMAP is a human counterpart of mouse KAP3 (kinesin superfamily-associated protein) that is associated with mouse KIF3A/B (a kinesin superfamily protein), which functions as a microtubule-based ATPase motor for organelle transport. A SMAP-interacting protein was isolated from a human brain cDNA library, it was identified as a human homolog of Xenopus XCAP-E (Xenopus chromosome-associated polypeptide), a subunit of condensins that regulate the assembly and structural maintenance of mitotic chromosomes, and named HCAP (Human chromosome-associated polypeptide). Tissue and subcellular distribution analyses indicate that HCAP is ubiquitously expressed and highly concentrated in the nuclear fraction, where SMAP and KIF3B are also present. SMAP was extracted as a ternary complex with HCAP and KIF3B from the nuclear fraction in the presence of Mg-ATP. The results suggest that SMAP/KAP3 serves as a linker between HCAP and KIF3A/B in the nucleus, and that SMAP/KAP3 plays a role in the interaction of chromosomes with an ATPase motor protein (Shimizu, 1998).
KIF3A is a classical member of the kinesin superfamily proteins (KIFs), ubiquitously expressed although predominantly in neural tissues, and which forms a heterotrimeric KIF3 complex with KIF3B or KIF3C and an associated protein, KAP3. To elucidate the function of the kif3A gene in vivo, kif3A knockout mice were made. kif3A-/- embryos displayed severe developmental abnormalities characterized by neural tube degeneration and mesodermal and caudal dysgenesis and died during the midgestational period at approximately 10.5 dpc (days post coitum), possibly resulting from cardiovascular insufficiency. Whole mount in situ hybridization of Pax6 revealed a normal pattern, while staining by sonic hedgehog (shh) and Brachyury (T) exhibited abnormal patterns in the anterior-posterior (A-P) direction at both mesencephalic and thoracic levels. These results suggest that KIF3A might be involved in mesodermal patterning and in turn neurogenesis (Takeda, 1999).
Kinesin superfamily proteins (KIFs) comprise several dozen molecular motor proteins. The KIF3 heterotrimer complex is one of the most abundantly and ubiquitously expressed KIFs in mammalian cells. To unveil the functions of KIF3, microinjection of function-blocking monovalent antibodies against KIF3 into cultured superior cervical ganglion (SCG) neurons was carried out. This treatment significantly blocked fast axonal transport and brought about inhibition of neurite extension. A yeast two-hybrid binding assay revealed the association of fodrin with the KIF3 motor through KAP3. This was further confirmed by using vesicles collected from large bundles of axons (cauda equina), from which membranous vesicles could be prepared in pure preparations. Both immunoprecipitation and immunoelectron microscopy indicated the colocalization of fodrin and KIF3 on the same vesicles, the results reinforcing the evidence that the cargo of the KIF3 motor consists of fodrin-associating vesicles. In addition, pulse-labeling study implied partial comigration of both molecules as fast flow components. Taken together, the KIF3 motor is engaged in fast axonal transport that conveys membranous components important for neurite extension (Takeda, 2000).
The tumor suppressor gene adenomatous polyposis coli (APC) is mutated in sporadic and familial colorectal tumours. APC is involved in the proteasome-mediated degradation of beta-catenin, through its interaction with beta-catenin, GSK-3 beta and Axin. APC also interacts with the microtubule cytoskeleton and has been localized to clusters near the distal ends of microtubules at the edges of migrating epithelial cells. Moreover, in Xenopus laevis epithelial cells, APC has been shown to move along microtubules and accumulate at their growing plus ends. However, the mechanism of APC accumulation and the nature of these APC clusters remain unknown. APC is shown to interact with the kinesin superfamily (KIF) 3A-KIF3B proteins, microtubule plus-end-directed motor proteins, through an association with the kinesin superfamily-associated protein 3 (KAP3). The interaction of APC with KAP3 was required for its accumulation in clusters, and mutant APCs derived from cancer cells were unable to accumulate efficiently in clusters. These results suggest that APC and beta-catenin are transported along microtubules by KAP3-KIF3A-KIF3B, accumulate in the tips of membrane protrusions, and may thus regulate cell migration (Jimbo, 2002).
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