Exploring the mechanistic and temporal regulation of LRP6 endocytosis in canonical WNT signaling
Abstract
Endocytosis plays a pivotal regulatory role in canonical WNT signaling. Internalization of the low-density lipoprotein receptor-related protein 6 (LRP6) receptor complex can either promote or attenuate canonical WNT signaling, depending on the employed internalization pathway. Detailed analysis of the mechanism of LRP6 internalization and its temporal regulation is crucial for understanding the different cellular responses to WNT stimulation under varying conditions and in various cell types. Here, we elucidate the mechanisms involved in the internalization of LRP6 and re-evaluate existing, partly contradicting, theories on the regulation of LRP6 receptor internalization. We utilize a computational approach that aims at finding a set of mechanisms that accounts for the temporal dynamics of LRP6 receptor internalization upon WNT stimulation. Starting with a simple simulation model, we successively extend and probe the model's behavior based on quantitative measurements. The final model confirms that LRP6 internalization is clathrin independent in vertebrates, is not restricted to microdomains, and that signalosome formation delays LRP6 internalization within the microdomains. These findings partly revise the current understanding of LRP6 internalization in vertebrates.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In two studies ([30, 56]) the simulation models were only validated (having assumed plausible ranges for parameter values).
“and in two studies ([30, 56]) they were only validated (having assumed plausible ranges for parameter values).”
From Relating simulation studies by provenance—Developing a family of Wnt signaling models (2021) · cites this paper as [56]
A second cluster forms around the simulation studies [45, 46, 51, 56, 57] and either includes the same wet-lab data from [105, 106], the Cell cycle [46] or ROS [51, 57].
“A second cluster forms around the simulation studies [45, 46, 51, 56, 57] and either includes the same wet-lab data from [105, 106], the Cell cycle [46] or ROS [51, 57].”
From Relating simulation studies by provenance—Developing a family of Wnt signaling models (2021) · cites this paper as [56]
Some studies develop a story line where a simulation model has been successively refined, extended, or composed ([28, 33, 34, 36, 41, 46, 48, 49, 51, 56]).
“Some studies develop a story line where a simulation model has been successively refined, extended, or composed ([28, 33, 34, 36, 41, 46, 48, 49, 51, 56]).”
From Relating simulation studies by provenance—Developing a family of Wnt signaling models (2021) · cites this paper as [56]
Cites
Wnt/β-Catenin Signaling: Components, Mechanisms, and Diseases
MacDonald, B. T., Tamai, K., & He, X. (2009) · Developmental Cell · doi:10.1016/j.devcel.2009.06.016 · Cited by 5,583 · see citing works
Wnt/β-catenin signaling and disease
Clevers, H., & Nusse, R. (2012) · Cell · doi:10.1016/j.cell.2012.05.012 · Cited by 5,554 · see citing works
The Wnt Signaling Pathway in Development and Disease
Logan, C. Y., & Nusse, R. (2004) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev.cellbio.20.010403.113126 · Cited by 5,325 · see citing works
Lipid rafts as a membrane-organizing principle
Lingwood, D., & Simons, K. (2010) · Science · doi:10.1126/science.1174621 · Cited by 4,417 · see citing works
Mechanics of Motor Proteins and the Cytoskeleton
Howard, & Clark (2002) · Applied Mechanics Reviews · doi:10.1115/1.1451234 · Cited by 2,909 · see citing works
WNT and β-catenin signalling: diseases and therapies
Moon, R. T., Kohn, A. D., Ferrari, G. V. D., & Kaykas, A. (2004) · Nature Reviews Genetics · doi:10.1038/nrg1427 · Cited by 1,763 · see citing works
Distinct endocytic pathways regulate TGF-β receptor signalling and turnover
Guglielmo, G. M. D., Roy, C. L., Goodfellow, A. F., & Wrana, J. L. (2003) · Nature Cell Biology · doi:10.1038/ncb975 · Cited by 1,152 · see citing works
Endocytosis and signalling: intertwining molecular networks
Sorkin, A. D., & von Zastrow, M. (2009) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2748 · Cited by 1,137 · see citing works
Wnt Induces LRP6 Signalosomes and Promotes Dishevelled-Dependent LRP6 Phosphorylation
Bilić, J., Huang, Y., Davidson, G. R., Zimmermann, T., Cruciat, C., Bienz, M., & Niehrs, C. (2007) · Science · doi:10.1126/science.1137065 · Cited by 923 · see citing works
Clathrin- and non-clathrin-mediated endocytic regulation of cell signalling
Roy, C. L., & Wrana, J. L. (2005) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1571 · Cited by 862 · see citing works
Receptors; models for binding, trafficking and signaling
(1997) · General Pharmacology The Vascular System · doi:10.1016/s0306-3623(97)90087-2 · Cited by 855 · see citing works
Novel mechanism of Wnt signalling inhibition mediated by Dickkopf-1 interaction with LRP6/Arrow
Bafico, A., Liu, G., Yaniv, A., Gazit, A., & Aaronson, S. A. (2001) · Nature Cell Biology · doi:10.1038/35083081 · Cited by 772 · see citing works
Head inducer Dickkopf-1 is a ligand for Wnt coreceptor LRP6
Semënov, M. V., Tamai, K., Brott, B. K., Kühl, M., Sokol, S. Y., & He, X. (2001) · Current Biology · doi:10.1016/s0960-9822(01)00290-1 · Cited by 700 · see citing works
Sabharanjak, S., Sharma, P., Parton, R. G., & Mayor, S. (2002) · Developmental Cell · doi:10.1016/s1534-5807(02)00145-4 · Cited by 647 · see citing works
Vincent Danos, A., & Laneve, C. (2004) · Theoretical Computer Science · doi:10.1016/j.tcs.2004.03.065 · Cited by 502 · see citing works
Endocytosis of Receptor Tyrosine KinasesPreprint
Goh, L. K., & Sorkin, A. D. (2013) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a017459 · Cited by 462 · see citing works
Ultrastructural identification of uncoated caveolin-independent early endocytic vehicles
Kirkham, M., Fujita, A., Chadda, R., Nixon, S. J., Kurzchalia, T. V., Sharma, D. K., Pagano, R. E., Hancock, J. F., Mayor, S., & Parton, R. G. (2005) · The Journal of Cell Biology · doi:10.1083/jcb.200407078 · Cited by 439 · see citing works
Lipid Rafts, Caveolae, and Their Endocytosis
Lajoie, P., & Nabi, I. R. (2010) · International review of cytology · doi:10.1016/s1937-6448(10)82003-9 · Cited by 370 · see citing works
Rules for Modeling Signal-Transduction Systems
Hlavacek, W. S., Faeder, J. R., Blinov, M. L., Posner, R. G., Hucka, M., & Fontana, W. (2006) · Science's STKE · doi:10.1126/stke.3442006re6 · Cited by 350 · see citing works
Caveolin Is Necessary for Wnt-3a-Dependent Internalization of LRP6 and Accumulation of β-Catenin
Yamamoto, H., Komekado, H., & Kikuchi, A. (2006) · Developmental Cell · doi:10.1016/j.devcel.2006.07.003 · Cited by 296 · see citing works
Molecular mechanisms of clathrin-independent endocytosis
Hansen, C. G., & Nichols, B. (2009) · Journal of Cell Science · doi:10.1242/jcs.033951 · Cited by 295 · see citing works
Yamamoto, H., Sakane, H., Yamamoto, H., Michiue, T., & Kikuchi, A. (2008) · Developmental Cell · doi:10.1016/j.devcel.2008.04.015 · Cited by 232 · see citing works
Bourhis, E., Tam, C., Franke, Y., Bazán, J. F., Ernst, J. A., Hwang, J., Costa, M., Cochran, A. G., & Hannoush, R. N. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.092130 · Cited by 230 · see citing works
A critical role for endocytosis in Wnt signaling
Blitzer, J. T., & Nusse, R. (2006) · BMC Cell Biology · doi:10.1186/1471-2121-7-28 · Cited by 221 · see citing works
Building endocytic pits without clathrin
Johannes, L., Parton, R. G., Bassereau, P. M., & Mayor, S. (2015) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3968 · Cited by 201 · see citing works
Rule-based multi-level modeling of cell biological systems
Maus, C., Rybacki, S., & Uhrmacher, A. M. (2011) · BMC Systems Biology · doi:10.1186/1752-0509-5-166 · Cited by 150 · see citing works
Self-citationÖzhan, G., Sezgin, E., Wehner, D., Pfister, A. S., Kühl, S. J., Kagermeier-Schenk, B., Kühl, M., Schwille, P., & Weidinger, G. (2013) · Developmental Cell · doi:10.1016/j.devcel.2013.07.020 · Cited by 112 · see citing works
Active organization of membrane constituents in living cells
Rao, M., & Mayor, S. (2014) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2014.05.007 · Cited by 111 · see citing works
The Kappa platform for rule-based modeling
Boutillier, P., Maasha, M., Li, X., Medina-Abarca, H. F., Krivine, J., Feret, J., Cristescu, I., Forbes, A. G., & Fontana, W. (2018) · Bioinformatics · doi:10.1093/bioinformatics/bty272 · Cited by 107 · see citing works
Brennan, K. R., González‐Sancho, J. M., Castelo‐Soccio, L. A., Howe, L. R., & Brown, A. M. C. (2004) · Oncogene · doi:10.1038/sj.onc.1207642 · Cited by 103 · see citing works
Sakane, H., Yamamoto, H., & Kikuchi, A. (2010) · Journal of Cell Science · doi:10.1242/jcs.058008 · Cited by 98 · see citing works
Kagermeier-Schenk, B., Wehner, D., Özhan, G., Yamamoto, H., Li, J., Kirchner, K., Hoffmann, C., Stern, P. L., Kikuchi, A., Schambony, A., et al. (2011) · Developmental Cell · doi:10.1016/j.devcel.2011.10.015 · Cited by 97 · see citing works
Rafting through traffic: Membrane domains in cellular logistics
Diaz-Rohrer, B. B., Levental, K. R., & Levental, I. (2014) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/j.bbamem.2014.07.029 · Cited by 90 · see citing works
The function of endocytosis in Wnt signaling
Brunt, L. H., & Scholpp, S. (2017) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-017-2654-2 · Cited by 83 · see citing works
Jiang, Y. Q., He, X., & Howe, P. H. (2012) · The EMBO Journal · doi:10.1038/emboj.2012.83 · Cited by 82 · see citing works
Endocytosis: A Positive or a Negative Influence on Wnt Signalling?
Gagliardi, M. E., Piddini, E., & Vincent, J. (2007) · Traffic · doi:10.1111/j.1600-0854.2007.00662.x · Cited by 81 · see citing works
Clathrin and AP2 are required for PtdIns(4,5)P2-mediated formation of LRP6 signalosomes
Kim, I., Pan, W., Jones, S. A., Zhang, Y., Zhuang, X., & Wu, D. (2013) · The Journal of Cell Biology · doi:10.1083/jcb.201206096 · Cited by 79 · see citing works
RAB8B Is Required for Activity and Caveolar Endocytosis of LRP6
Demir, K., Kirsch, N., Beretta, C. A., Erdmann, G., Ingelfinger, D., Moro, E., Argenton, F., Carl, M., Niehrs, C., & Boutros, M. (2013) · Cell Reports · doi:10.1016/j.celrep.2013.08.008 · Cited by 78 · see citing works
Ewald, R., & Uhrmacher, A. (2014) · ACM Transactions on Modeling and Computer Simulation · doi:10.1145/2567895 · Cited by 75 · see citing works
Self-citationKhan, Z., Vijayakumar, S., de la Torre, T. V., Rotolo, S., & Bafico, A. (2007) · Molecular and Cellular Biology · doi:10.1128/mcb.00773-07 · Cited by 73 · see citing works
Sphingolipids and membrane environments for caveolin
Sonnino, S., & Prinetti, A. (2009) · FEBS Letters · doi:10.1016/j.febslet.2009.01.007 · Cited by 70 · see citing works
Haack, F., Lemcke, H., Ewald, R., Rharass, T., & Uhrmacher, A. M. (2015) · PLOS Computational Biology · doi:10.1371/journal.pcbi.1004106 · Cited by 66 · see citing works
Self-citationKeeping Wnt Signalosome in Check by Vesicular Traffic
Feng, Q., & Gao, N. (2014) · Journal of Cellular Physiology · doi:10.1002/jcp.24853 · Cited by 59 · see citing works
Hagemann, A. I. H., Kurz, J., Kauffeld, S., Chen, Q., Reeves, P. M., Weber, S., Schindler, S., Davidson, G. R., Kirchhausen, T. L., & Scholpp, S. (2014) · Journal of Cell Science · doi:10.1242/jcs.148767 · Cited by 59 · see citing works
Sezgin, E., Azbazdar, Y., Ng, X. W., Teh, C., Simons, K., Weidinger, G., Wohland, T., Eggeling, C., & Özhan, G. (2017) · FEBS Journal · doi:10.1111/febs.14139 · Cited by 51 · see citing works
Liu, C., Kanekiyo, T., Roth, B., & Bu, G. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.533927 · Cited by 41 · see citing works
Toward a comprehensive language for biological systems
Faeder, J. R. (2011) · BMC Biology · doi:10.1186/1741-7007-9-68 · Cited by 41 · see citing works
Semantics and Efficient Simulation Algorithms of an Expressive Multilevel Modeling Language
Helms, T., Warnke, T., Maus, C., & Uhrmacher, A. M. (2017) · ACM Transactions on Modeling and Computer Simulation · doi:10.1145/2998499 · Cited by 34 · see citing works
Self-citationMultisite EGFR phosphorylation is regulated by adaptor protein abundances and dimer lifetimes
Salazar-Cavazos, E., Nitta, C. F., Mitra, E. D., Wilson, B. S., Lidke, K. A., Hlavacek, W. S., & Lidke, D. S. (2020) · Molecular Biology of the Cell · doi:10.1091/mbc.e19-09-0548 · Cited by 32 · see citing works
Lloyd‐Lewis, B., Fletcher, A. G., Dale, T. C., & Byrne, H. M. (2013) · WIREs Systems Biology and Medicine · doi:10.1002/wsbm.1221 · Cited by 31 · see citing works
Provenance in modeling and simulation studies — Bridging gaps
Ruscheinski, A., & Uhrmacher, A. (2017) · 2017 Winter Simulation Conference (WSC) · doi:10.1109/wsc.2017.8247839 · Cited by 31 · see citing works
Self-citationElucidating the Sources of β-Catenin Dynamics in Human Neural Progenitor Cells
Mazemondet, O., John, M., Leye, S., Rolfs, A., & Uhrmacher, A. M. (2012) · PLoS ONE · doi:10.1371/journal.pone.0042792 · Cited by 25 · see citing works
Self-citationAzbazdar, Y., Özalp, Ö., Sezgin, E., Veerapathiran, S., Duncan, A. L., Sansom, M. S. P., Eggeling, C., Wohland, T., Karaca, E., & Özhan, G. (2019) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2019.00281 · Cited by 22 · see citing works
Ruscheinski, A., Wilsdorf, P., Dombrowsky, M., & Uhrmacher, A. M. (2019) · ACM/IEEE/SCS Workshop on Principles of Advanced and Distributed Simulation (PADS) · doi:10.1145/3316480.3325514 · Cited by 20 · see citing works
Self-citationYamamoto, H., Umeda, D., Matsumoto, S., & Kikuchi, A. (2017) · Journal of Cell Science · doi:10.1242/jcs.202135 · Cited by 11 · see citing works
Reproducible and flexible simulation experiments with ML-Rules and SESSL
Warnke, T., Helms, T., & Uhrmacher, A. M. (2018) · Bioinformatics · doi:10.1093/bioinformatics/btx741 · Cited by 9 · see citing works
Self-citationCOMPLEX SIMULATION EXPERIMENTS MADE EASY
Warnke, T., & Uhrmacher, A. M. (2018) · Winter Simulation Conference · doi:10.1109/wsc.2018.8632429 · Cited by 9 · see citing works
Self-citationComplex simulation experiments made easy
Warnke, T., & Uhrmacher, A. M. (2018) · Winter Simulation Conference · doi:10.5555/3320516.3320575 · Cited by 5 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Regulation of Wnt receptor activity: Implications for therapeutic development in colon cancer
Zhong, Z. A., Michalski, M. N., Stevens, P. D., Sall, E. A., & Williams, B. O. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.100782 · Cited by 46 · see citing works
A Model-Driven Approach for Conducting Simulation Experiments
Wilsdorf, P., Heller, J., Budde, K., Zimmermann, J., Warnke, T., Haubelt, C. D., Timmermann, D., van Rienen, U., & Uhrmacher, A. M. (2022) · Applied Sciences · doi:10.3390/app12167977 · Cited by 23 · see citing works
Self-citationRelating simulation studies by provenance—Developing a family of Wnt signaling models
Budde, K., Smith, J., Wilsdorf, P., Haack, F., & Uhrmacher, A. M. (2021) · PLOS Computational Biology · doi:10.1371/journal.pcbi.1009227 · Cited by 23 · see citing works
“A second cluster forms around the simulation studies [45, 46, 51, 56, 57] and either includes the same wet-lab data from [105, 106], the Cell cycle [46] or ROS [51, 57].”
BackgroundMethodInfluentialSelf-citationContext, Composition, Automation, and Communication: The C 2 AC Roadmap for Modeling and Simulation
Uhrmacher, A. M., Frazier, P. I., Hähnle, R., Klügl, F., Lorig, F., Ludäscher, B., Nenzi, L., Ruiz-Martín, C., Rumpe⋆, B., Szabo, C., et al. (2024) · ACM Transactions on Modeling and Computer Simulation · doi:10.1145/3673226 · Cited by 21 · see citing works
Self-citationWnt signalling and endocytosis: Mechanisms, controversies and implications for stress responses
Wu, Y., Chiang, Y., Chou, S., & Pan, C. (2020) · Biology of the Cell · doi:10.1111/boc.202000099 · Cited by 8 · see citing works
Potential and Challenges of Assurance Cases for Simulation Validation
Wilsdorf, P., Zschaler, S., Haack, F., & Uhrmacher, A. M. (2024) · Winter Simulation Conference · doi:10.1109/wsc63780.2024.10838818 · Cited by 6 · see citing works
Self-citationOptimizing Wnt activation in fetal calf serum (FCS)-free organoid expansion media
Liefting, E. J. M., & Bajramovic, J. J. (2025) · Frontiers in Toxicology · doi:10.3389/ftox.2025.1504469 · Cited by 4 · see citing works
Simulation studies of social systems: telling the story based on provenance patterns
Wilsdorf, P., Reinhardt, O., Prike, T., Hinsch, M., Bijak, J., & Uhrmacher, A. M. (2024) · Royal Society Open Science · doi:10.1098/rsos.240258 · Cited by 4 · see citing works
Self-citationSimulation Studies of Social Systems – Telling the Story Based on Provenance PatternsPreprint
Reinhardt, O., Prike, T., Hinsch, M., Bijak, J., Wilsdorf, P., & Uhrmacher, A. M. (2022) · doi:10.36227/techrxiv.20209844 · Cited by 4 · see citing works
Self-citationChallenges and promises of self-adaptive simulation models
Uhrmacher, A. M., Wilsdorf, P., & Kreikemeyer, J. N. (2024) · SIMULATION · doi:10.1177/00375497241296878 · Cited by 3 · see citing works
Self-citationSimulation Studies of Social Systems -- Telling the Story Based on Provenance PatternsPreprint
Reinhardt, O., Prike, T., Hinsch, M., Bijak, J., Uhrmacher, A. M., & Wilsdorf, P. (2023) · doi:10.36227/techrxiv.20209844.v2 · Cited by 3 · see citing works
Self-citationTowards dialectic models for documenting and conducting simulation studies: A vision
Zschaler, S., Wilsdorf, P., Godfrey, T. E., & Uhrmacher, A. M. (2025) · ACM/IEEE/SCS Workshop on Principles of Advanced and Distributed Simulation (PADS) · doi:10.1145/3726301.3728411 · Cited by 2 · see citing works
Self-citationSIMPROV: Provenance capturing for simulation studies
Ruscheinski, A., Wolpers, A., Henning, P., Wilsdorf, P., & Uhrmacher, A. M. (2025) · PLoS ONE · doi:10.1371/journal.pone.0327607 · Cited by 1 · see citing works
Self-citationSimulation Studies of Social Systems -- Telling the Story Based on ProvenancePreprint
Reinhardt, O., Prike, T., Hinsch, M., Bijak, J., Uhrmacher, A. M., & Wilsdorf, P. (2022) · doi:10.36227/techrxiv.20209844.v1 · Cited by 1 · see citing works
Self-citationKöster, T., & Uhrmacher, A. M. (2023) · ACM/IEEE/SCS Workshop on Principles of Advanced and Distributed Simulation (PADS) · doi:10.1145/3573900.3593630
Self-citationHaack, F., Burrage, K., & Uhrmacher, A. M. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.11.20.689481
Self-citationGoal-Oriented Generation of Simulation Experiments
Wolpers, A., Wilsdorf, P., Haack, F., & Uhrmacher, A. M. (2025) · Winter Simulation Conference · doi:10.1109/wsc68292.2025.11338941
Self-citationDialectic Models for Documenting and Conducting Simulation Studies: Exploring Feasibility
Zschaler, S., Wilsdorf, P., Godfrey, T., & Uhrmacher, A. M. (2025) · Winter Simulation Conference · doi:10.1109/wsc68292.2025.11339048
Self-citation
- Authors
- Haack, F., Budde, K., & Uhrmacher, A. M.
- Affiliations
- University of Rostock (DE)
- Venue
- Journal of Cell Science
- Publisher
- The Company of Biologists
- Published
- 2020-08-01
- Volume
- 133
- Issue
- 15
- ISSN
- 0021-9533 (ISSN-L)
- 1477-9137
- OpenAlex
- W3041421316
- Cited by
- 18
- References
- 58
- Citations by year
- 2025: 6 · 2024: 4 · 2023: 2 · 2022: 3 · 2021: 2 · 2020: 1
- FWCI
- 0.65
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Cell Science (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft (SFB 1270/1–299150580)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- LRP6, endocytosis, Wnt/β-catenin signaling, receptor internalization, clathrin-independent endocytosis, signalosome, lipid rafts, microdomains, temporal regulation, computational modeling, vertebrates
- MeSH terms
- Animals, Clathrin, Endocytosis, Wnt Proteins, beta Catenin, Wnt Signaling Pathway, Low Density Lipoprotein Receptor-Related Protein-6
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
