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Wan-xi Yang - One of the best experts on this subject based on the ideXlab platform.
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KIF3A regulates the Wnt/β-catenin pathway via transporting β-catenin during spermatogenesis in Eriocheir sinensis.
Cell and tissue research, 2020Co-Authors: Ya-jing Liang, Fuqing Tan, Lan-min Wang, Wan-xi YangAbstract:The Wnt/β-catenin pathway participates in many important physiological events such as cell proliferation and differentiation in the male reproductive system. We found that Kinesin-2 motor KIF3A is highly expressed during spermatogenesis in Eriocheir sinensis; it may potentially promote the intracellular transport of cargoes in this process. However, only a few studies have focused on the relationship between KIF3A and the Wnt/β-catenin pathway in the male reproductive system of decapod crustaceans. In this study, we cloned and characterized the CDS of β-catenin in E. sinensis for the first time. Fluorescence in situ hybridization and immunofluorescence results showed the colocalization of Es-KIF3A and Es-β-catenin at the mRNA and the protein level respectively. To further explore the regulatory function of Es-KIF3A to the Wnt/β-catenin pathway, the es-KIF3A was knocked down by double-stranded RNA (dsRNA) in vivo and in primary cultured cells in testes of E. sinensis. Results showed that the expression of es-β-catenin and es-dvl were decreased in the es-KIF3A knockdown group. The protein expression level of Es-β-catenin was also reduced and the location of Es-β-catenin was changed from nucleus to cytoplasm in the late stage of spermatogenesis when es-KIF3A was knocked down. Besides, the co-IP result demonstrated that Es-KIF3A could bind with Es-β-catenin. In summary, this study indicates that Es-KIF3A can positively regulate the Wnt/β-catenin pathway during spermatogenesis and Es-KIF3A can bind with Es-β-catenin to facilitate the nuclear translocation of Es-β-catenin.
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KIF3A regulates the wnt β catenin pathway via transporting β catenin during spermatogenesis in eriocheir sinensis
Cell and Tissue Research, 2020Co-Authors: Ya-jing Liang, Fuqing Tan, Lan-min Wang, Wan-xi YangAbstract:The Wnt/β-catenin pathway participates in many important physiological events such as cell proliferation and differentiation in the male reproductive system. We found that Kinesin-2 motor KIF3A is highly expressed during spermatogenesis in Eriocheir sinensis; it may potentially promote the intracellular transport of cargoes in this process. However, only a few studies have focused on the relationship between KIF3A and the Wnt/β-catenin pathway in the male reproductive system of decapod crustaceans. In this study, we cloned and characterized the CDS of β-catenin in E. sinensis for the first time. Fluorescence in situ hybridization and immunofluorescence results showed the colocalization of Es-KIF3A and Es-β-catenin at the mRNA and the protein level respectively. To further explore the regulatory function of Es-KIF3A to the Wnt/β-catenin pathway, the es-KIF3A was knocked down by double-stranded RNA (dsRNA) in vivo and in primary cultured cells in testes of E. sinensis. Results showed that the expression of es-β-catenin and es-dvl were decreased in the es-KIF3A knockdown group. The protein expression level of Es-β-catenin was also reduced and the location of Es-β-catenin was changed from nucleus to cytoplasm in the late stage of spermatogenesis when es-KIF3A was knocked down. Besides, the co-IP result demonstrated that Es-KIF3A could bind with Es-β-catenin. In summary, this study indicates that Es-KIF3A can positively regulate the Wnt/β-catenin pathway during spermatogenesis and Es-KIF3A can bind with Es-β-catenin to facilitate the nuclear translocation of Es-β-catenin.
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Functional Analysis of KIF3A and KIF3B during Spermiogenesis of Chinese Mitten Crab Eriocheir sinensis
PloS one, 2014Co-Authors: Qi Wang, Da-hui Wang, Hong Zhou, Wan-xi YangAbstract:Background Spermatogenesis represents the transformation process at the level of cellular development. KIF3A and KIF3B are believed to play some roles in the assembly and maintenance of flagella, intracellular transport of materials including organelles and proteins, and other unknown functions during this process. During spermatogenesis in Eriocheir sinensis, if the sperm shaping machinery is dependent on KIF3A and KIF3B remains unknown.
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molecular characterization of a KIF3A like kinesin gene in the testis of the chinese fire bellied newt cynops orientalis
Molecular Biology Reports, 2012Co-Authors: Fuqing Tan, Da-hui Wang, Mei Liu, Wan-xi YangAbstract:KIF3A, the subunit within the kinesin-2 superfamily, is a typically N-terminal motor protein, which is involved in membranous organelle and intraflagellar transport. During spermatogenesis, KIF3A plays a critical role in the formation of flagella and cilia. KIF3A is also related to the left–right asymmetry, the signal pathway, DNA damage and tumorigenesis. We used RT-PCR and in situ hybridization to clone the KIF3A gene, and we identified its function in the testis of the Chinese fire-bellied newt Cynops orientalis (termed as co-KIF3A). The full-length sequence of co-KIF3A was 2193 bp, containing a 56 bp 5′UTR, 2073 bp ORF encoding a protein of 691 amino acids and a 64 bp 3′UTR. The secondary structure analysis showed that co-KIF3A had three motor domains, representing the N-terminal motor domain (1–400 aa), α-helix domain (400–600 aa) and C-terminal tail domain (600–691 aa). The amino acid sequence of co-KIF3A shared an identity of 55.9%, 90.9%, 89.9%, 91.3% and 85.7% with its counterparts in Aedes aegypti, Mus musculus, Xenopus tropicalis, Homo sapiens and Danio rerio, respectively. The calculated molecular weight of the putative co-KIF3A was 79 kDa and its estimated isoelectric point was 6.8. RT-PCR result showed that co-KIF3A was expressed in several examined tissues, with a high level in the testis and low levels in liver, muscle and ovum. KIF3A was weakly expressed in the heart and spleen, and barely detected in the intestine. In situ hybridization analysis demonstrated that in early spermatid co-KIF3A was expressed around the nuclear membrane. When the tail began to emerge in the middle spermatid, mRNA transcript was abundantly concentrated in the flagellum. The mRNA signal was still very strong along all the flagellum in late spermatid. In mature spermatid, the message was weak. Therefore, co-KIF3A probably plays a functional role in the spermiogenesis of C. orientalis.
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Identification and dynamic transcription of KIF3A homologue gene in spermiogenesis of Octopus tankahkeei.
Comparative biochemistry and physiology. Part A Molecular & integrative physiology, 2010Co-Authors: Wei Wang, Jun-quan Zhu, Ran Dang, Wan-xi YangAbstract:Abstract KIF3A is a subunit of the heterotrimeric Kinesin-II motor which achieves fame for its pivotal roles in the assembly and maintenance of cilia and flagella and in intracellular transport of membrane bound organelles and protein complexes in various tissues. Its intimacy to the cell's antenna, namely the primary cilia, makes it also involved in some signaling transduction pathways. To test the idea that KIF3A functions during spermiogenesis of the octopod Octopus tankahkeei , we hereby identified a gene (designated as ot-KIF3A ) encoding a protein apparently homologous to a group of KIF3As, from the testis of this organism. The full-length ot-KIF3A comprised a 344 bp 5' untranslated region, a 2241 bp open reading frame and a 147 bp 3' untranslated region. The putative protein consisted of 746 amino acid residues with a calculated molecular weight of 85 kDa and a predicted isoelectric point of 6.36. It shared an overall sequence identity of 69%, 69%, 69% and 67% to KIF3A from Homo sapiens , Rattus norvegicus , Mus musculus and Danio rerio , respectively. Tissue distribution profile analysis unraveled its presence in all the tissues examined. In situ hybridization of mRNA in spermionenic cells demonstrated that ot-KIF3A was expressed moderately at the beginning of spermiogenesis. The abundance of transcripts increased in intermediate spermatid and peaked in drastically remodeling and final spermatids. In mature sperm, the message was still visible in the head and tail. The temporal and spatial expression dynamics of ot-KIF3A during spermiogenesis supports the possibility that the putative motor protein, OtKIF3A, participates in the major cytological events during this differentiation program and is vital for the acquisition of the final cellular phenotype.
Minsuh Kim - One of the best experts on this subject based on the ideXlab platform.
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KIF3A binds to β-arrestin for suppressing Wnt/β-catenin signalling independently of primary cilia in lung cancer
Scientific reports, 2016Co-Authors: Minsuh Kim, Young-ah Suh, Bo Ra Lee, Joon Kim, Jin JangAbstract:Aberrant Wnt/β-catenin signalling is implicated in the progression of several human cancers, including non-small cell lung cancer (NSCLC). However, mutations in Wnt/β-catenin pathway components are uncommon in NSCLC, and their epigenetic control remains unclear. Here, we show that KIF3A, a member of the kinesin-2 family, plays a role in suppressing Wnt/β-catenin signalling in NSCLC cells. KIF3A knockdown increases both β-catenin levels and transcriptional activity with concomitant promotion of malignant potential, such as increased proliferation and migration and upregulation of stemness markers. Because KIF3A binds β-arrestin, KIF3A depletion allows β-arrestin to form a complex with DVL2 and axin, stabilizing β-catenin. Although primary cilia, whose biogenesis requires KIF3A, are thought to restrain the Wnt response, pharmacological inhibition of ciliogenesis failed to increase β-catenin activity in NSCLC cells. A correlation between KIF3A loss and a poorer NSCLC prognosis as well as β-catenin and cyclin D1 upregulation further suggests that KIF3A suppresses Wnt/β-catenin signalling and tumourigenesis in NSCLC.
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KIF3A binds to β arrestin for suppressing wnt β catenin signalling independently of primary cilia in lung cancer
Scientific Reports, 2016Co-Authors: Minsuh Kim, Young-ah Suh, Bo Ra Lee, Joon Kim, Se Jin JangAbstract:Aberrant Wnt/β-catenin signalling is implicated in the progression of several human cancers, including non-small cell lung cancer (NSCLC). However, mutations in Wnt/β-catenin pathway components are uncommon in NSCLC, and their epigenetic control remains unclear. Here, we show that KIF3A, a member of the kinesin-2 family, plays a role in suppressing Wnt/β-catenin signalling in NSCLC cells. KIF3A knockdown increases both β-catenin levels and transcriptional activity with concomitant promotion of malignant potential, such as increased proliferation and migration and upregulation of stemness markers. Because KIF3A binds β-arrestin, KIF3A depletion allows β-arrestin to form a complex with DVL2 and axin, stabilizing β-catenin. Although primary cilia, whose biogenesis requires KIF3A, are thought to restrain the Wnt response, pharmacological inhibition of ciliogenesis failed to increase β-catenin activity in NSCLC cells. A correlation between KIF3A loss and a poorer NSCLC prognosis as well as β-catenin and cyclin D1 upregulation further suggests that KIF3A suppresses Wnt/β-catenin signalling and tumourigenesis in NSCLC.
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Abstract 1176: The role of KIF3A in the suppression of canonical Wnt signaling through the KIF3A and β-arrestin complex, independent of the ciliary mechanism, in non-small cell lung cancer (NSCLC)
Molecular and Cellular Biology Genetics, 2016Co-Authors: Minsuh Kim, Bo Ra Lee, Joon Kim, Yong-ah Suh, Jin JangAbstract:Aberrant Wnt/β-catenin signaling is implicated in the progression of several human cancers, including non-small-cell lung cancer (NSCLC). However, mutations in Wnt/β-catenin pathway com-ponents are uncommon in NSCLC, and epigenetic mechanisms controlling the Wnt/β-catenin path-way remain unclear. Here, we show that KIF3A, a member of the kinesin-2 motor family, plays a key role in suppressing Wnt/β-catenin signaling in NSCLC cells. Knockdown of KIF3A increases both β-catenin levels and transcriptional activity, with a concomitant promotion of malignant phenotypes, such as enhanced proliferation and migration, and upregulation of stemness markers. KIF3A binds to β-arrestin, and KIF3A depletion allows β-arrestin to form a complex with DVL2 and AXIN, result-ing in β-catenin stabilization. Although primary cilia, of which the biogenesis requires KIF3A, are thought to restrain the Wnt response, pharmacological inhibition of ciliogenesis does not enhance β-catenin activity in NSCLC cells. A correlation between KIF3A loss and worse NSCLC prognosis as well as upregulation of β-catenin and Cyclin D1 further suggests that KIF3A is a suppressor of Wnt/β-catenin signaling and tumorigenesis in NSCLC. Citation Format: Minsuh Kim, Yong-Ah Suh, Ju-hee Oh, Bo Ra Lee, Joon Kim, Se Jin Jang. The role of KIF3A in the suppression of canonical Wnt signaling through the KIF3A and β-arrestin complex, independent of the ciliary mechanism, in non-small cell lung cancer (NSCLC). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1176.
Jin Jang - One of the best experts on this subject based on the ideXlab platform.
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KIF3A binds to β-arrestin for suppressing Wnt/β-catenin signalling independently of primary cilia in lung cancer
Scientific reports, 2016Co-Authors: Minsuh Kim, Young-ah Suh, Bo Ra Lee, Joon Kim, Jin JangAbstract:Aberrant Wnt/β-catenin signalling is implicated in the progression of several human cancers, including non-small cell lung cancer (NSCLC). However, mutations in Wnt/β-catenin pathway components are uncommon in NSCLC, and their epigenetic control remains unclear. Here, we show that KIF3A, a member of the kinesin-2 family, plays a role in suppressing Wnt/β-catenin signalling in NSCLC cells. KIF3A knockdown increases both β-catenin levels and transcriptional activity with concomitant promotion of malignant potential, such as increased proliferation and migration and upregulation of stemness markers. Because KIF3A binds β-arrestin, KIF3A depletion allows β-arrestin to form a complex with DVL2 and axin, stabilizing β-catenin. Although primary cilia, whose biogenesis requires KIF3A, are thought to restrain the Wnt response, pharmacological inhibition of ciliogenesis failed to increase β-catenin activity in NSCLC cells. A correlation between KIF3A loss and a poorer NSCLC prognosis as well as β-catenin and cyclin D1 upregulation further suggests that KIF3A suppresses Wnt/β-catenin signalling and tumourigenesis in NSCLC.
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Abstract 1176: The role of KIF3A in the suppression of canonical Wnt signaling through the KIF3A and β-arrestin complex, independent of the ciliary mechanism, in non-small cell lung cancer (NSCLC)
Molecular and Cellular Biology Genetics, 2016Co-Authors: Minsuh Kim, Bo Ra Lee, Joon Kim, Yong-ah Suh, Jin JangAbstract:Aberrant Wnt/β-catenin signaling is implicated in the progression of several human cancers, including non-small-cell lung cancer (NSCLC). However, mutations in Wnt/β-catenin pathway com-ponents are uncommon in NSCLC, and epigenetic mechanisms controlling the Wnt/β-catenin path-way remain unclear. Here, we show that KIF3A, a member of the kinesin-2 motor family, plays a key role in suppressing Wnt/β-catenin signaling in NSCLC cells. Knockdown of KIF3A increases both β-catenin levels and transcriptional activity, with a concomitant promotion of malignant phenotypes, such as enhanced proliferation and migration, and upregulation of stemness markers. KIF3A binds to β-arrestin, and KIF3A depletion allows β-arrestin to form a complex with DVL2 and AXIN, result-ing in β-catenin stabilization. Although primary cilia, of which the biogenesis requires KIF3A, are thought to restrain the Wnt response, pharmacological inhibition of ciliogenesis does not enhance β-catenin activity in NSCLC cells. A correlation between KIF3A loss and worse NSCLC prognosis as well as upregulation of β-catenin and Cyclin D1 further suggests that KIF3A is a suppressor of Wnt/β-catenin signaling and tumorigenesis in NSCLC. Citation Format: Minsuh Kim, Yong-Ah Suh, Ju-hee Oh, Bo Ra Lee, Joon Kim, Se Jin Jang. The role of KIF3A in the suppression of canonical Wnt signaling through the KIF3A and β-arrestin complex, independent of the ciliary mechanism, in non-small cell lung cancer (NSCLC). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1176.
Nobutaka Hirokawa - One of the best experts on this subject based on the ideXlab platform.
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the spatiotemporal construction of the axon initial segment via kif3 kap3 trim46 transport under mark2 signaling
Cell Reports, 2019Co-Authors: Sotaro Ichinose, Nobutaka Hirokawa, Tadayuki Ogawa, Xuguang JiangAbstract:Summary The axon initial segment (AIS) is a compartment that serves as a molecular barrier to achieve axon-dendrite differentiation. Distribution of specific proteins during early neuronal development has been proposed to be critical for AIS construction. However, it remains unknown how these proteins are specifically targeted to the proximal axon within this limited time period. Here, we reveal spatiotemporal regulation driven by the microtubule (MT)-based motor KIF3A/B/KAP3 that transports TRIM46, influenced by a specific MARK2 phosphorylation cascade. In the proximal part of the future axon under low MARK2 activity, the KIF3/KAP3 motor recognizes TRIM46 as cargo and transports it to the future AIS. In contrast, in the somatodendritic area under high MARK2 activity, KAP3 phosphorylated at serine 60 by MARK2 cannot bind with TRIM46 and be transported. This spatiotemporal regulation between KIF3/KAP3 and TRIM46 under specific MARK2 activity underlies the specific transport needed for axonal differentiation.
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Mechanism of Activity-Dependent Cargo Loading via the Phosphorylation of KIF3A by PKA and CaMKIIa
Neuron, 2015Co-Authors: Sotaro Ichinose, Tadayuki Ogawa, Nobutaka HirokawaAbstract:A regulated mechanism of cargo loading is crucial for intracellular transport. N-cadherin, a synaptic adhesion molecule that is critical for neuronal function, must be precisely transported to dendritic spines in response to synaptic activity and plasticity. However, the mechanism of activity-dependent cargo loading remains unclear. To elucidate this mechanism, we investigated the activity-dependent transport of N-cadherin via its transporter, KIF3A. First, by comparing KIF3A-bound cargo vesicles with unbound KIF3A, we identified critical KIF3A phosphorylation sites and specific kinases, PKA and CaMKIIa, using quantitative phosphoanalyses. Next, mutagenesis and kinase inhibitor experiments revealed that N-cadherin transport was enhanced via phosphorylation of the KIF3A C terminus, thereby increasing cargo-loading activity. Furthermore, N-cadherin transport was enhanced during homeostatic upregulation of synaptic strength, triggered by chronic inactivation by TTX. We propose the first model of activity-dependent cargo loading, in which phosphorylation of the KIF3A C terminus upregulates the loading and transport of N-cadherin in homeostatic synaptic plasticity.
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Intracellular transport, molecular motors, KIFs and related diseases
BMC Genomics, 2014Co-Authors: Nobutaka HirokawaAbstract:The intracellular transport is fundamental for cellular functions, morphogenesis and survival in general including neurons composed of a very long axon and dendrites. We discovered most of the kinesin superfamily motor proteins, KIFs, 45 genes in mammals, elucidated their molecular structures and functional roles by molecular cell biology, molecular genetics, biophysics and structural biology and successfully disclosed the mechanism of intracellular transport fundamental for neuronal functions. In the axon and dendrites KIFs transport their cargos such as synaptic vesicle precursors (KIF1A/KIF1Bbeta), mitochondria (KIF1Balpha/KIF5s), plasma membrane proteins (KIF3/KIF5s), NMDA glutamate receptors (KIF17), AMPA receptors (KIF5s) and mRNA with large protein complex (KIF5s). KIFs mainly recognize and bind their cargoes through adaptor protein complex and release them via phosphorylation of KIFs or GTP hydrolyses of cargo G-protein. Furthermore, using molecular genetics we successfully uncovered that KIFs play significant roles for fundamental physiological phenomena in development and functions of nervous system and that deletion of KIFs causes certain diseases by clarifying followings: 1) KIF1A/KIF1B beta hetero mice serve as a model for neuropathy, 2) KIF3 determines left/right asymmetry by generating cilia and nodal flow in the node of early embryos, 3) KIF17 plays a fundamental role on learning and memory by not only transporting NMDA glutamate receptor in dendrites but also controlling transcription and translation of KIF17 and NMDA receptor mRNAs by enhancing phosphorylated CREB, 4) KIF1A is essential for hippocampal synaptogenesis and learning enhancement in an enriched environment, 5) KIF2A is fundamental for brain wiring by controlling unnecessary elongation of growth cones by depolymerizing microtubules, 6) KIF4 plays a crucial role in the activity-dependent survival of postmitotic neurons in brain development by regulating poly(ADP-ribose) polymerase-1 activity, 7) KIF26A is essential for enteric neuronal development by regulating GDNF-Ret signaling, 8) KIF3 suppresses tumorigenesis by transporting beta-catenin from Golgi to plasma membrane for serving as cell-cell adhesion molecules, inhibiting its accumulation in the nucleus and suppressing hyper proliferation of progenitor cells, 9)KIF5A is essential for GABAa receptor transport and KIF5A deletion causes epilepsy, 10)KIF19A is a microtubule depolymerizing KIF for ciliary length control and its deletion causes female infertility and hydrocephalus based on affected fluid flows, 11)KIF13A transports serotonin receptors to plasma membranes and its deletion causes elevated–anxiety phenotypes. Thus, KIFs play significant roles not only at cellular level, but also in brain function and development. Further, their malfunctions cause diseases such as neuropathy, epilepsy, dementia, elevated anxiety, tumor, megacolon and hydrocephalus.
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Kinesin superfamily proteins and their various functions and dynamics
Experimental cell research, 2004Co-Authors: Nobutaka Hirokawa, Reiko TakemuraAbstract:Kinesin superfamily proteins (KIFs) are motor proteins that transport membranous organelles and macromolecules fundamental for cellular functions along microtubules. Their roles in transport in axons and dendrites have been studied extensively, but KIFs are also used in intracellular transport in general. Recent findings have revealed that in many cases, the specific interaction of cargoes and motors is mediated via adaptor/scaffolding proteins. Cargoes are sorted to precise destinations, such as axons or dendrites. KIFs also participate in polarized transport in epithelial cells as shown in the apical transport of annexin XIIIb-containing vesicles by KIFC3. KIFs play important roles in higher order neuronal activity; transgenic mice overexpressing KIF17, which transports N-methyl-d-asp (NMDA) receptors to dendrites, show enhanced memory and learning. KIFs also play significant roles in neuronal development and brain wiring: KIF2A suppresses elongation of axon collaterals by its unique microtubule-depolymerizing activity. X-ray crystallography has revealed the structural uniqueness of KIF2 underlying the microtubule-depolymerizing activity. In addition, single molecule biophysics and optical trapping have shown that the motility of monomeric KIF1A is caused by biased Brownian movement, and X-ray crystallography has shown how the conformational changes occur for KIF1A to move during ATP hydrolysis. These multiple approaches in analyzing KIF functions will illuminate many basic mechanisms underlying intracellular events and will be a very promising and fruitful area for future studies.
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left right asymmetry and kinesin superfamily protein KIF3A new insights in determination of laterality and mesoderm induction by KIF3A mice analysis
Journal of Cell Biology, 1999Co-Authors: Sen Takeda, Yoshiaki Yonekawa, Yosuke Tanaka, Yasushi Okada, Shigenori Nonaka, Nobutaka HirokawaAbstract: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, we made KIF3A knockout mice. KIF3A −/− embryos displayed severe developmental abnormalities characterized by neural tube degeneration and mesodermal and caudal dysgenesis and died during the midgestational period at ∼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.
Joon Kim - One of the best experts on this subject based on the ideXlab platform.
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KIF3A binds to β-arrestin for suppressing Wnt/β-catenin signalling independently of primary cilia in lung cancer
Scientific reports, 2016Co-Authors: Minsuh Kim, Young-ah Suh, Bo Ra Lee, Joon Kim, Jin JangAbstract:Aberrant Wnt/β-catenin signalling is implicated in the progression of several human cancers, including non-small cell lung cancer (NSCLC). However, mutations in Wnt/β-catenin pathway components are uncommon in NSCLC, and their epigenetic control remains unclear. Here, we show that KIF3A, a member of the kinesin-2 family, plays a role in suppressing Wnt/β-catenin signalling in NSCLC cells. KIF3A knockdown increases both β-catenin levels and transcriptional activity with concomitant promotion of malignant potential, such as increased proliferation and migration and upregulation of stemness markers. Because KIF3A binds β-arrestin, KIF3A depletion allows β-arrestin to form a complex with DVL2 and axin, stabilizing β-catenin. Although primary cilia, whose biogenesis requires KIF3A, are thought to restrain the Wnt response, pharmacological inhibition of ciliogenesis failed to increase β-catenin activity in NSCLC cells. A correlation between KIF3A loss and a poorer NSCLC prognosis as well as β-catenin and cyclin D1 upregulation further suggests that KIF3A suppresses Wnt/β-catenin signalling and tumourigenesis in NSCLC.
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KIF3A binds to β arrestin for suppressing wnt β catenin signalling independently of primary cilia in lung cancer
Scientific Reports, 2016Co-Authors: Minsuh Kim, Young-ah Suh, Bo Ra Lee, Joon Kim, Se Jin JangAbstract:Aberrant Wnt/β-catenin signalling is implicated in the progression of several human cancers, including non-small cell lung cancer (NSCLC). However, mutations in Wnt/β-catenin pathway components are uncommon in NSCLC, and their epigenetic control remains unclear. Here, we show that KIF3A, a member of the kinesin-2 family, plays a role in suppressing Wnt/β-catenin signalling in NSCLC cells. KIF3A knockdown increases both β-catenin levels and transcriptional activity with concomitant promotion of malignant potential, such as increased proliferation and migration and upregulation of stemness markers. Because KIF3A binds β-arrestin, KIF3A depletion allows β-arrestin to form a complex with DVL2 and axin, stabilizing β-catenin. Although primary cilia, whose biogenesis requires KIF3A, are thought to restrain the Wnt response, pharmacological inhibition of ciliogenesis failed to increase β-catenin activity in NSCLC cells. A correlation between KIF3A loss and a poorer NSCLC prognosis as well as β-catenin and cyclin D1 upregulation further suggests that KIF3A suppresses Wnt/β-catenin signalling and tumourigenesis in NSCLC.
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Abstract 1176: The role of KIF3A in the suppression of canonical Wnt signaling through the KIF3A and β-arrestin complex, independent of the ciliary mechanism, in non-small cell lung cancer (NSCLC)
Molecular and Cellular Biology Genetics, 2016Co-Authors: Minsuh Kim, Bo Ra Lee, Joon Kim, Yong-ah Suh, Jin JangAbstract:Aberrant Wnt/β-catenin signaling is implicated in the progression of several human cancers, including non-small-cell lung cancer (NSCLC). However, mutations in Wnt/β-catenin pathway com-ponents are uncommon in NSCLC, and epigenetic mechanisms controlling the Wnt/β-catenin path-way remain unclear. Here, we show that KIF3A, a member of the kinesin-2 motor family, plays a key role in suppressing Wnt/β-catenin signaling in NSCLC cells. Knockdown of KIF3A increases both β-catenin levels and transcriptional activity, with a concomitant promotion of malignant phenotypes, such as enhanced proliferation and migration, and upregulation of stemness markers. KIF3A binds to β-arrestin, and KIF3A depletion allows β-arrestin to form a complex with DVL2 and AXIN, result-ing in β-catenin stabilization. Although primary cilia, of which the biogenesis requires KIF3A, are thought to restrain the Wnt response, pharmacological inhibition of ciliogenesis does not enhance β-catenin activity in NSCLC cells. A correlation between KIF3A loss and worse NSCLC prognosis as well as upregulation of β-catenin and Cyclin D1 further suggests that KIF3A is a suppressor of Wnt/β-catenin signaling and tumorigenesis in NSCLC. Citation Format: Minsuh Kim, Yong-Ah Suh, Ju-hee Oh, Bo Ra Lee, Joon Kim, Se Jin Jang. The role of KIF3A in the suppression of canonical Wnt signaling through the KIF3A and β-arrestin complex, independent of the ciliary mechanism, in non-small cell lung cancer (NSCLC). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1176.
