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The kinesin-4 protein Kif7 regulates mammalian Hedgehog signalling by organizing the cilium tip compartment
Open accessAbstract
Mammalian Hedgehog (Hh) signal transduction requires a primary cilium, a microtubule-based organelle, and the Gli-Sufu complexes that mediate Hh signalling, which are enriched at cilia tips. Kif7, a kinesin-4 family protein, is a conserved regulator of the Hh signalling pathway and a human ciliopathy protein. Here we show that Kif7 localizes to the cilium tip, the site of microtubule plus ends, where it limits cilium length and controls cilium structure. Purified recombinant Kif7 binds the plus ends of growing microtubules in vitro, where it reduces the rate of microtubule growth and increases the frequency of microtubule catastrophe. Kif7 is not required for normal intraflagellar transport or for trafficking of Hh pathway proteins into cilia. Instead, a central function of Kif7 in the mammalian Hh pathway is to control cilium architecture and to create a single cilium tip compartment, where Gli-Sufu activity can be correctly regulated.
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“β-arrestins are adaptor proteins that are recruited to the proximal C-terminus of GPR161 in a manner dependent on G protein-coupled receptor kinase 2 (GRK2)138.”
From Cellular signalling by primary cilia in development, organ function and disease (2019) · cites this paper as [138]
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“GPR161 is also removed from primary cilia in a SMO-dependent and β-arrestin-dependent manner following activation of HH signalling 28, 138.”
From Cellular signalling by primary cilia in development, organ function and disease (2019) · cites this paper as [138]
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Citations
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Dysfunction of the ciliary ARMC9/TOGARAM1 protein module causes Joubert syndrome
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BackgroundResultInfluentialDynarrestin, a Novel Inhibitor of Cytoplasmic Dynein
Höing, S., Yeh, T., Baumann, M., Martinez, N. E., Habenberger, P., Kremer, L., Drexler, H. C. A., Küchler, P., Reinhardt, P., Choidas, A., et al. (2018) · Cell chemical biology · doi:10.1016/j.chembiol.2017.12.014 · Cited by 78
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MethodInfluentialPrimary Cilia Are Dysfunctional in Obese Adipose-Derived Mesenchymal Stem Cells
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Ghiretti, A. E., Thies, E., Tokito, M. K., Lin, T., Ostap, E. M., Kneussel, M., & Holzbaur, E. L. F. (2016) · Neuron · doi:10.1016/j.neuron.2016.10.003 · Cited by 72
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InfluentialRoutes and machinery of primary cilium biogenesis
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“It is intriguing to note that elongated cilia have also been found in a wide range of other ciliopathy models including: Bbs-4 null mice (18), jckmice (19), Meckel syndrome (20), Kif7 mutated cells (21), and JBTS secondary to KIAA0556 mutations (22), suggesting elongated primary cilia may be a widespread feature of ci…”
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Weghe, J. C. V. D., Gómez, A. E., & Doherty, D. (2022) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev-genom-121321-093528 · Cited by 69
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“Cells depleted of KIF7 (JBTSF12) and KIAA0556 (JBTS26) also have extended axonemes (34,35).”
BackgroundProteins that control the geometry of microtubules at the ends of cilia
Louka, P., Vasudevan, K. K., Guha, M., Joachimiak, E., Włoga, D., Tomasi, R. F.-X., Baroud, C. N., Dupuis‐Williams, P., Galati, D. F., Pearson, C. G., et al. (2018) · The Journal of Cell Biology · doi:10.1083/jcb.201804141 · Cited by 64
“KIF7 may contribute to the distal segment organization by shortening the ends of axonemal microtubules (He et al., 2014).”
BackgroundInfluentialCilia and polycystic kidney disease
Ma, M. (2020) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2020.05.003 · Cited by 72
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The Hedgehog Signaling Pathway in Idiopathic Pulmonary Fibrosis: Resurrection Time
Effendi, W. I., & Nagano, T. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms23010171 · Cited by 59
“The core components that mediate the Hh signal response in vertebrae are two patched receptors (Ptch1, Ptch2), a key signal transducer smoothened receptor (Smo), three glioma-associated oncogene (Gli) transcription factors (Gli1, Gli2, Gli3), the suppressed fusion homolog (Sufu), and kinesine protein 7 (Kif7) [14].”
BackgroundInfluentialThe multifaceted roles of primary cilia in the development of the cerebral cortex
Hasenpusch-Theil, K., & Theil, T. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.630161 · Cited by 66
“Primary cilia are pivotal to interneuron migration since disrupting ciliary functions in cortical interneurons interfered with the migratory process and led to abnormal positioning of interneurons in the adult cortex (Baudoin et al., 2012; Higginbotham et al., 2012).”
BackgroundKinesin-4 KIF21B is a potent microtubule pausing factor
van Riel, W. E., Rai, A., Bianchi, S., Katrukha, E. A., Liu, Q., Heck, A. J. R., Hoogenraad, C. C., Steinmetz, M. O., Kapitein, L. C., & Akhmanova, A. S. (2017) · eLife · doi:10.7554/elife.24746 · Cited by 63
“Another kinesin-4 family member, KIF7, is immotile; it participates in organizing the tips of ciliary MTs by reducing the MT growth rate and promoting catastrophes (He et al., 2014).”
The hedgehog pathway and ocular developmental anomalies
Cavodeassi, F., Creuzet, S., & Etchevers, H. (2018) · Human Genetics · doi:10.1007/s00439-018-1918-8 · Cited by 67
Shortened primary cilium length and dysregulated Sonic hedgehog signaling in Niemann-Pick C1 disease
Canterini, S., Dragotto, J., Dardis, A., Zampieri, S., Stefano, M. E. D., Mangia, F., Erickson, R. P., & Fiorenza, M. T. (2017) · Human Molecular Genetics · doi:10.1093/hmg/ddx118 · Cited by 63
Mori, R. D., Romani, M., D’Arrigo, S., Zaki, M. S., Lorefice, E., Tardivo, S., Biagini, T., Stanley, V., Musaev, D., Fluss, J., et al. (2017) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2017.08.017 · Cited by 64
“In the absence of functional KIF7, the ciliary tip compartment becomes disorganized, leading to the formation of ectopic tip-like compartments where GLI-SUFU complexes localize and are inappropriately activated even in the absence of SHH ligand.(52) The same constellation of cranio-facial abnormalities along with deve…”
BackgroundHarris, J. A., Liu, Y., Yang, P., Kner, P., & Lechtreck, K. F. (2015) · Molecular Biology of the Cell · doi:10.1091/mbc.e15-08-0608 · Cited by 62
Control of meiotic chromosomal bouquet and germ cell morphogenesis by the zygotene cilium
Mytlis, A., Kumar, V., Qiu, T., Deis, R., Hart, N., Levy, K., Masek, M., Shawahny, A., Ahmad, A., Eitan, H., et al. (2022) · Science · doi:10.1126/science.abh3104 · Cited by 60
The intraflagellar transport cycle
Lacey, S. E., & Pigino, G. (2024) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-024-00797-x · Cited by 74
“Once at the tip, KIF7 establishes a specialized signalling compartment 26,156,158 that results in activation of GLI2, which can elicit a transcriptional response back in the cell body 12 .”
Liu, Y. C., Couzens, A. L., Deshwar, A. R., McBroom, L. D. B., Zhang, X., Puviindran, V., Scott, I. C., Gingras, A., Hui, C., & Angers, S. (2014) · Science Signaling · doi:10.1126/scisignal.2005608 · Cited by 57
Cilia Distal Domain: Diversity in Evolutionarily Conserved Structures
Soares, H., Carmona, B., Nolasco, S., Melo, L. V., & Gonçalves, J. (2019) · Cells · doi:10.3390/cells8020160 · Cited by 63
“KIF7 displays no motility, is unable to diffuse along microtubules [199], localizes to the base of primary cilium in the absence of Hh signaling, and shows an Hh depending-accumulation at the ciliary tip [198].”
InfluentialThe developmental biology of kinesins
Konjikusic, M. J., Gray, R. S., & Wallingford, J. B. (2020) · Developmental Biology · doi:10.1016/j.ydbio.2020.09.009 · Cited by 59
The role of Hedgehog and Notch signaling pathway in cancer
Xia, R., Xu, M., Yang, J., & Ma, X. (2022) · Molecular Biomedicine · doi:10.1186/s43556-022-00099-8 · Cited by 62
Kinesin superfamily proteins and the regulation of microtubule dynamics in morphogenesis
Niwa, S. (2014) · Anatomical Science International · doi:10.1007/s12565-014-0259-5 · Cited by 58
“Actually, a recent study has shown that KIF7, a member of Kinesin-4, regulates the length of primary cilia (He et al. 2014).”
BackgroundTaylor, S. P., Bosakova, M. K., Vařecha, M., Bálek, L., Bárta, T., Trantı́rek, L., Jelínková, I., Durán, I., Veselá, I., Forlenza, K. N., et al. (2016) · Human Molecular Genetics · doi:10.1093/hmg/ddw240 · Cited by 54
“twisted, similar to the structures of cilia from Kif7 mutants Kif7 and Kif7 (39), suggesting that ICK may be required for ciliary structural integrity.”
BackgroundBowie, E., Norris, R., Anderson, K. V., & Goetz, S. C. (2018) · PLoS Genetics · doi:10.1371/journal.pgen.1007844 · Cited by 51
Self-citationRab34 GTPase mediates ciliary membrane formation in the intracellular ciliogenesis pathway
Ganga, A. K., Kennedy, M. C., Oguchi, M. E., Gray, S. D., Oliver, K. E., Knight, T. A., Cruz, E. M. D. L., Homma, Y., Fukuda, M., & Breslow, D. K. (2021) · Current Biology · doi:10.1016/j.cub.2021.04.075 · Cited by 53
Schwarz, T., Prieler, B. E. M., Schmid, J. A., Grzmil, P., & Neesen, J. (2017) · European Journal of Cell Biology · doi:10.1016/j.ejcb.2017.02.003 · Cited by 53
“For the induction of cilia formation in NIH 3T3 cells confluent cultures were serum starved for 24 h prior further analysis (He et al., 2014).”
MethodKinesin-4 KIF21B limits microtubule growth to allow rapid centrosome polarization in T cells
Hooikaas, P. J., Damstra, H. G. J., Gros, O., van Riel, W. E., Martin, M., Smits, Y. T., van Loosdregt, J., Kapitein, L. C., Berger, F., & Akhmanova, A. S. (2020) · eLife · doi:10.7554/elife.62876 · Cited by 53
“Kinesin-4 family members are well known for their ability to limit MT growth in a variety of cellular processes (Bieling et al., 2010; Bringmann et al., 2004; He et al., 2014; Yue et al., 2018).”
BackgroundRegulation of ciliary membrane protein trafficking and signalling by kinesin motor proteins
Morthorst, S. K., Christensen, S. T., & Pedersen, L. B. (2018) · The FEBS Journal · doi:10.1111/febs.14583 · Cited by 49
Intraflagellar transport is deeply integrated in hedgehog signaling
Eguether, T., Cordelières, F. P., & Pazour, G. J. (2018) · Molecular Biology of the Cell · doi:10.1091/mbc.e17-10-0600 · Cited by 56
“Like Gli2, Kif7 and SuFu also localize to the ciliary tip, and the amount at the tip increases on pathway activation (Haycraft et al., 2005; He et al., 2014).”
BackgroundThe hedgehog pathway in nonalcoholic fatty liver disease
Machado, M. V., & Diehl, A. M. (2018) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.1080/10409238.2018.1448752 · Cited by 52
“Kif7, which also localizes to the tip of the PC when Smo is active, enhances Gli–Sufu localization in this compartment (He et al. 2014), and full-length Gli dissociates from Sufu, moves back to the cytoplasm, and enters the nucleus, where it promotes the transcription of several genes, including…”
BackgroundA CEP104-CSPP1 Complex Is Required for Formation of Primary Cilia Competent in Hedgehog Signaling
Frikstad, K.-A. M., Molinari, E., Thoresen, M., Ramsbottom, S. A., Hughes, F. E. P., Letteboer, S. J. F., Gilani, S., Schink, K. O., Stokke, T., Geimer, S., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.07.025 · Cited by 50
“Speculatively, the CSPP-L/CEP104 complex hence opposes KIF7 and KIAA0556mediated axoneme growth restriction at the ciliary tip (He et al., 2014; Sanders et al., 2015).”
BackgroundInfluentialKanamaru, T., Neuner, A., Kurtulmus, B., & Pereira, G. (2021) · The EMBO Journal · doi:10.15252/embj.2021108843 · Cited by 43
Hedgehog signaling: From basic research to clinical applications
Yao, E., & Chuang, P. (2015) · Journal of the Formosan Medical Association · doi:10.1016/j.jfma.2015.01.005 · Cited by 51
“Kif7 controls cilium architecture at the tip and this could affect Sufu-Gli activity.(78) New tools are needed in order to establish the function of ciliary localization of Hh pathway components.”
BackgroundThe heterotrimeric kinesin-2 complex interacts with and regulates GLI protein function
Carpenter, B. S., Barry, R. L., Verhey, K. J., & Allen, B. L. (2015) · Journal of Cell Science · doi:10.1242/jcs.162552 · Cited by 49
“However, given that KIF7 does not possess plus-end-directed microtubule motor activity (He et al., 2014), one possibility is that KAP3–GLI protein interactions are disrupted in Kif7-mutant cells owing to the disorganized ciliary tip compartments.”
BackgroundResultInfluentialHan, Y., Xiong, Y., Shi, X., Wu, J. I., Zhao, Y., & Jiang, J. (2017) · PLoS Biology · doi:10.1371/journal.pbio.2002063 · Cited by 48
Cell Cycle-Related Kinase (CCRK) regulates ciliogenesis and Hedgehog signaling in mice
Snouffer, A., Brown, D. A., Lee, H., Walsh, J. D., Lupu, F. I., Norman, R. X., Lechtreck, K. F., Ko, H. W., & Eggenschwiler, J. T. (2017) · PLoS Genetics · doi:10.1371/journal.pgen.1006912 · Cited by 47
“Although loss of the ciliary kinesin Kif7 and loss of CCRK each cause deregulation of ciliary length, their effects on Hh pathway activity and neural patterning are largely opposite from one another [43, 44].”
Wormser, O., Gradstein, L., Yogev, Y., Perez, Y., Kadir, R., Goliand, I., Sadaka, Y., Riati, S. E., Flusser, H., Nachmias, D., et al. (2019) · European Journal of Human Genetics · doi:10.1038/s41431-019-0347-z · Cited by 48
Goetz, S. C., Bangs, F. K., Barrington, C. L., Katsanis, N., & Anderson, K. V. (2017) · PLoS ONE · doi:10.1371/journal.pone.0173399 · Cited by 47
Self-citationTruncated SALL1 Impedes Primary Cilia Function in Townes-Brocks Syndrome
Bozal‐Basterra, L., Martín‐Ruiz, I., Pirone, L., Liang, Y., Sigurðsson, J. O., Gonzalez-Santamarta, M., Giordano, I., Gabicagogeascoa, E., de Luca, A., Rodríguez, J. A., et al. (2018) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2017.12.017 · Cited by 46
Self-citationInvolvement of Wnt signaling in primary cilia assembly and disassembly
Lee, K. H. (2020) · FEBS Journal · doi:10.1111/febs.15579 · Cited by 41
Ververis, A., Christodoulou, A., Christoforou, M., Kamilari, C., Lederer, C. W., & Santama, N. (2015) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-015-1980-5 · Cited by 41
Causes, costs and consequences of kinesin motors communicating through the microtubule lattice
Verhey, K. J., & Ohi, R. (2023) · Journal of Cell Science · doi:10.1242/jcs.260735 · Cited by 37
Ritter, A., Kreis, N., Roth, S., Friemel, A., Jennewein, L., Eichbaum, C., Solbach, C., Louwen, F., & Yuan, J. (2019) · Stem Cell Research & Therapy · doi:10.1186/s13287-019-1373-z · Cited by 40
Metadata
- Authors
- He, M., Subramanian, R., Bangs, F., Omelchenko, T., Liem Jr, K. F., Kapoor, T. M., & Anderson, K. V.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Rockefeller University (US)
- Corresponding author
- Anderson, Kathryn V.
- Venue
- Nature Cell Biology
- Published
- 2014-06-22
- Volume
- 16
- Issue
- 7
- Pages
- 663-672
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- PMC
- PMC4085576
- OpenAlex
- W2083616180
- Cited by
- 302
- References
- 55
- Citations by year
- 2026: 14 · 2025: 20 · 2024: 20 · 2023: 13 · 2022: 30 · 2021: 26 · 2020: 26 · 2019: 27 · 2018: 31 · 2017: 34 · 2016: 22 · 2015: 32 · 2014: 7
- FWCI
- 20.74
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (P30CA008748)
- National Institute of General Medical Sciences (R01GM065933, GM65933)
- National Institute of Neurological Disorders and Stroke (NS044385, R01NS044385)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Kidney Cyst Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Hedgehog Signaling Pathway Studies
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cystic Fibrosis Research Advances
- Keywords
- KIF7, kinesin-4, Hedgehog signaling, primary cilia, microtubule plus ends, ciliopathies, intraflagellar transport, ciliary trafficking
- MeSH terms
- Animals, Cell Line, Cells, Cultured, Cilia, Fibroblasts, Humans, Microtubules, Mutation, Protein Binding, Recombinant Proteins, Signal Transduction, Kinesins, Protein Transport, NIH 3T3 Cells, Mice, Hedgehog Proteins, Axoneme, HEK293 Cells
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