{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T17:18:12Z","timestamp":1788801492400,"version":"build-2803163510"},"reference-count":73,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2019,8,6]],"date-time":"2019-08-06T00:00:00Z","timestamp":1565049600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2019,8,6]],"date-time":"2019-08-06T00:00:00Z","timestamp":1565049600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Clarendon Arab Bank"},{"name":"EPA research fund"},{"name":"Oxford Doctoral Training Centre"},{"DOI":"10.13039\/501100000265","name":"RCUK | Medical Research Council","doi-asserted-by":"publisher","award":["MRC Oxford CIC"],"award-info":[{"award-number":["MRC Oxford CIC"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000289","name":"Cancer Research UK","doi-asserted-by":"publisher","award":["C429"],"award-info":[{"award-number":["C429"]}],"id":[{"id":"10.13039\/501100000289","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000289","name":"Cancer Research UK","doi-asserted-by":"publisher","award":["C429"],"award-info":[{"award-number":["C429"]}],"id":[{"id":"10.13039\/501100000289","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Clarendon Arab Bank (MS) Oxford Doctoral Training Centre (MD) EPA research trust"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The cation-independent mannose 6-phosphate\/insulin-like growth factor-2 receptor (M6P\/IGF2R or IGF2R) traffics IGF2 and M6P ligands between pre-lysosomal and extra-cellular compartments. Specific IGF2 and M6P high-affinity binding occurs via domain-11 and domains-3-5-9, respectively. Mammalian maternal <jats:italic>Igf2r<\/jats:italic> allele expression exceeds the paternal allele due to imprinting (silencing). <jats:italic>Igf2r<\/jats:italic> null-allele maternal transmission results in placenta and heart over-growth and perinatal lethality (&gt;90%) due to raised extra-cellular IGF2 secondary to impaired ligand clearance. It remains unknown if the phenotype is due to\u00a0either ligand alone, or to both ligands. Here, we evaluate <jats:italic>Igf2r<\/jats:italic> specific loss-of-function of the domain-11 IGF2 binding site by replacing isoleucine with alanine in the CD loop (exon 34, I1565A), a mutation also detected in cancers. <jats:italic>Igf2r<\/jats:italic><jats:sup><jats:italic>I1565A<\/jats:italic>\/+<jats:italic>p<\/jats:italic><\/jats:sup> maternal transmission (heterozygote), resulted in placental and embryonic over-growth with reduced neonatal lethality (&lt;60%), and long-term survival. The perinatal mortality (&gt;80%) observed in homozygotes (<jats:italic>Igf2r<\/jats:italic><jats:sup><jats:italic>I1565A\/I1565A<\/jats:italic><\/jats:sup>) suggested that wild-type paternal allele expression attenuates the heterozygote phenotype. To evaluate <jats:italic>Igf2r<\/jats:italic> tumour suppressor function, we utilised intestinal adenoma models known to be <jats:italic>Igf2<\/jats:italic> dependent. Bi-allelic <jats:italic>Igf2r<\/jats:italic> expression suppressed intestinal adenoma (<jats:italic>Apc<\/jats:italic><jats:sup><jats:italic>Min<\/jats:italic><\/jats:sup>). <jats:italic>Igf2r<\/jats:italic><jats:sup><jats:italic>I1565A<\/jats:italic>\/+<jats:italic>p<\/jats:italic><\/jats:sup> in a conditional model (<jats:italic>Lgr5-Cre<\/jats:italic>, <jats:italic>Apc<\/jats:italic><jats:sup><jats:italic>loxp\/loxp<\/jats:italic><\/jats:sup>) resulted in worse survival and increased adenoma proliferation. Growth, survival and intestinal adenoma appear dependent on IGF2R<jats:italic>-<\/jats:italic>domain-11 IGF2 binding.<\/jats:p>","DOI":"10.1038\/s41598-019-47827-9","type":"journal-article","created":{"date-parts":[[2019,8,6]],"date-time":"2019-08-06T10:22:49Z","timestamp":1565086969000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Maternal transmission of an Igf2r domain 11: IGF2 binding mutant allele (Igf2rI1565A) results in partial lethality, overgrowth and intestinal adenoma progression"],"prefix":"10.1038","volume":"9","author":[{"given":"Jennifer","family":"Hughes","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7101-984X","authenticated-orcid":false,"given":"Mirvat","family":"Surakhy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sermet","family":"Can","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Ducker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nick","family":"Davies","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francis","family":"Szele","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"B\u00fchnemann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0825-2793","authenticated-orcid":false,"given":"Emma","family":"Carter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roman","family":"Trikin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7868-5818","authenticated-orcid":false,"given":"Matthew P.","family":"Crump","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susana","family":"Frago","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. Bassim","family":"Hassan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,8,6]]},"reference":[{"key":"47827_CR1","doi-asserted-by":"publisher","first-page":"202","DOI":"10.1038\/nrm1050","volume":"4","author":"P Ghosh","year":"2003","unstructured":"Ghosh, P., Dahms, N. M. & Kornfeld, S. Mannose 6-phosphate receptors: new twists in the tale. Nat Rev Mol Cell Biol 4, 202\u2013212 (2003).","journal-title":"Nat Rev Mol Cell Biol"},{"key":"47827_CR2","doi-asserted-by":"publisher","first-page":"1209","DOI":"10.1126\/science.1228633","volume":"338","author":"C Williams","year":"2012","unstructured":"Williams, C. et al. An exon splice enhancer primes IGF2:IGF2R binding site structure and function evolution. Science 338, 1209\u20131213 (2012).","journal-title":"Science"},{"key":"47827_CR3","doi-asserted-by":"publisher","first-page":"1045","DOI":"10.1016\/0092-8674(91)90256-X","volume":"64","author":"D Haig","year":"1991","unstructured":"Haig, D. & Graham, C. Genomic imprinting and the strange case of the insulin-like growth factor II receptor. Cell 64, 1045\u20131046 (1991).","journal-title":"Cell"},{"key":"47827_CR4","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1038\/349084a0","volume":"349","author":"DP Barlow","year":"1991","unstructured":"Barlow, D. P., Stoger, R., Herrmann, B. G., Saito, K. & Schweifer, N. The mouse insulin-like growth factor type-2 receptor is imprinted and closely linked to the Tme locus. Nature 349, 84\u201387 (1991).","journal-title":"Nature"},{"key":"47827_CR5","doi-asserted-by":"publisher","first-page":"3128","DOI":"10.1101\/gad.11.23.3128","volume":"11","author":"J Eggenschwiler","year":"1997","unstructured":"Eggenschwiler, J. et al. Mouse mutant embryos overexpressing IGF-II exhibit phenotypic features of the Beckwith-Wiedemann and Simpson-Golabi-Behmel syndromes. Genes Dev 11, 3128\u20133142 (1997).","journal-title":"Genes Dev"},{"key":"47827_CR6","doi-asserted-by":"publisher","first-page":"e57270","DOI":"10.1371\/journal.pone.0057270","volume":"8","author":"J Hughes","year":"2013","unstructured":"Hughes, J., Frago, S., Buhnemann, C., Carter, E. J. & Hassan, A. B. Maternal transmission of a humanised Igf2r allele results in an Igf2 dependent hypomorphic and non-viable growth phenotype. PLoS One 8, e57270 (2013).","journal-title":"PLoS One"},{"key":"47827_CR7","doi-asserted-by":"publisher","first-page":"2953","DOI":"10.1101\/gad.8.24.2953","volume":"8","author":"MM Lau","year":"1994","unstructured":"Lau, M. M. et al. Loss of the imprinted IGF2\/cation-independent mannose 6-phosphate receptor results in fetal overgrowth and perinatal lethality. Genes Dev 8, 2953\u20132963 (1994).","journal-title":"Genes Dev"},{"issue":"2","key":"47827_CR8","doi-asserted-by":"publisher","first-page":"517","DOI":"10.1006\/dbio.1996.0182","volume":"177","author":"Thomas Ludwig","year":"1996","unstructured":"Ludwig, T. et al. Mouse mutants lacking the type 2 IGF receptor (IGF2R) are rescued from perinatal lethality in Igf2 and Igf1r null backgrounds. Dev-Biol 177, 517\u2013535 issn: 0012-1606, (1996).","journal-title":"Developmental Biology"},{"key":"47827_CR9","doi-asserted-by":"crossref","first-page":"1881","DOI":"10.1242\/dev.128.10.1881","volume":"128","author":"A Wutz","year":"2001","unstructured":"Wutz, A. et al. Non-imprinted Igf2r expression decreases growth and rescues the Tme mutation in mice. Development 128, 1881\u20131887 (2001).","journal-title":"Development"},{"key":"47827_CR10","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1016\/S0002-9440(10)63823-0","volume":"162","author":"AA Wylie","year":"2003","unstructured":"Wylie, A. A. et al. Tissue-specific inactivation of murine M6P\/IGF2R. Am J Pathol 162, 321\u2013328 (2003).","journal-title":"Am J Pathol"},{"key":"47827_CR11","doi-asserted-by":"publisher","first-page":"836","DOI":"10.1016\/j.ygeno.2004.07.007","volume":"84","author":"JP Hagan","year":"2004","unstructured":"Hagan, J. P., Kozlov, S. V., Chiang, Y., Sewell, L. & Stewart, C. L. Intraspecific mating with CzechII\/Ei mice rescue lethality associated with loss of function mutations of the imprinted genes, Igf2r and Cdkn1c. Genomics 84, 836\u2013843 (2004).","journal-title":"Genomics"},{"key":"47827_CR12","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1242\/dev.110.1.151","volume":"110","author":"JE Lee","year":"1990","unstructured":"Lee, J. E., Pintar, J. & Efstratiadis, A. Pattern of the insulin-like growth factor II gene expression during early mouse embryogenesis. Development 110, 151\u2013159 (1990).","journal-title":"Development"},{"key":"47827_CR13","doi-asserted-by":"publisher","first-page":"1795","DOI":"10.1242\/dev.054338","volume":"138","author":"P Li","year":"2011","unstructured":"Li, P. et al. IGF signaling directs ventricular cardiomyocyte proliferation during embryonic heart development. Development 138, 1795\u20131805 (2011).","journal-title":"Development"},{"key":"47827_CR14","doi-asserted-by":"publisher","first-page":"1187","DOI":"10.1242\/dev.00997","volume":"131","author":"CA Conover","year":"2004","unstructured":"Conover, C. A. et al. Metalloproteinase pregnancy-associated plasma protein A is a critical growth regulatory factor during fetal development. Development 131, 1187\u20131194 (2004).","journal-title":"Development"},{"key":"47827_CR15","doi-asserted-by":"publisher","first-page":"359","DOI":"10.1038\/nrg1062","volume":"4","author":"JF Wilkins","year":"2003","unstructured":"Wilkins, J. F. & Haig, D. What good is genomic imprinting: the function of parent-specific gene expression. Nat Rev Genet 4, 359\u2013368 (2003).","journal-title":"Nat Rev Genet"},{"key":"47827_CR16","doi-asserted-by":"publisher","first-page":"437","DOI":"10.1242\/dev.032060","volume":"136","author":"PA Latos","year":"2009","unstructured":"Latos, P. A. et al. An in vitro ES cell imprinting model shows that imprinted expression of the Igf2r gene arises from an allele-specific expression bias. Development 136, 437\u2013448 (2009).","journal-title":"Development"},{"key":"47827_CR17","doi-asserted-by":"publisher","first-page":"810","DOI":"10.1038\/415810a","volume":"415","author":"F Sleutels","year":"2002","unstructured":"Sleutels, F., Zwart, R. & Barlow, D. P. The non-coding Air RNA is required for silencing autosomal imprinted genes. Nature 415, 810\u2013813 (2002).","journal-title":"Nature"},{"key":"47827_CR18","doi-asserted-by":"publisher","first-page":"3116","DOI":"10.1038\/emboj.2008.239","volume":"27","author":"SH Stricker","year":"2008","unstructured":"Stricker, S. H. et al. Silencing and transcriptional properties of the imprinted Airn ncRNA are independent of the endogenous promoter. EMBO J 27, 3116\u20133128 (2008).","journal-title":"EMBO J"},{"key":"47827_CR19","doi-asserted-by":"publisher","first-page":"745","DOI":"10.1038\/39631","volume":"389","author":"A Wutz","year":"1997","unstructured":"Wutz, A. et al. Imprinted expression of the Igf2r gene depends on an intronic CpG island. Nature 389, 745\u2013749 (1997).","journal-title":"Nature"},{"key":"47827_CR20","doi-asserted-by":"publisher","first-page":"1940","DOI":"10.1158\/0008-5472.CAN-05-2036","volume":"66","author":"J Harper","year":"2006","unstructured":"Harper, J. et al. Soluble IGF2 receptor rescues Apc(Min\/+) intestinal adenoma progression induced by Igf2 loss of imprinting. Cancer Res 66, 1940\u20131948 (2006).","journal-title":"Cancer Res"},{"key":"47827_CR21","doi-asserted-by":"publisher","first-page":"1678","DOI":"10.1002\/mrd.20909","volume":"75","author":"DD Pravtcheva","year":"2008","unstructured":"Pravtcheva, D. D. & Wise, T. L. Igf2r improves the survival and transmission ratio of Igf2 transgenic mice. Mol Reprod Dev 75, 1678\u20131687 (2008).","journal-title":"Mol Reprod Dev"},{"key":"47827_CR22","doi-asserted-by":"publisher","first-page":"28610","DOI":"10.1074\/jbc.273.44.28610","volume":"273","author":"S Zaina","year":"1998","unstructured":"Zaina, S. & Squire, S. The soluble type 2 insulin-like growth factor (IGF-II) receptor reduces organ size by IGF-II-mediated and IGF-II-independent mechanisms. J Biol Chem 273, 28610\u201328616 (1998).","journal-title":"J Biol Chem"},{"key":"47827_CR23","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1038\/84769","volume":"27","author":"LE Young","year":"2001","unstructured":"Young, L. E. et al. Epigenetic change in IGF2R is associated with fetal overgrowth after sheep embryo culture. Nat Genet 27, 153\u2013154 (2001).","journal-title":"Nat Genet"},{"key":"47827_CR24","doi-asserted-by":"publisher","first-page":"971","DOI":"10.1038\/ng.168","volume":"40","author":"G Smits","year":"2008","unstructured":"Smits, G. et al. Conservation of the H19 noncoding RNA and H19-IGF2 imprinting mechanism in therians. Nat Genet 40, 971\u2013976 (2008).","journal-title":"Nat Genet"},{"key":"47827_CR25","doi-asserted-by":"publisher","first-page":"345","DOI":"10.1038\/nature12303","volume":"500","author":"A Venkatraman","year":"2013","unstructured":"Venkatraman, A. et al. Maternal imprinting at the H19-Igf2 locus maintains adult haematopoietic stem cell quiescence. Nature 500, 345\u2013349 (2013).","journal-title":"Nature"},{"key":"47827_CR26","doi-asserted-by":"publisher","first-page":"1006","DOI":"10.1038\/ncb3399","volume":"18","author":"S Dror","year":"2016","unstructured":"Dror, S. et al. Melanoma miRNA trafficking controls tumour primary niche formation. Nat Cell Biol 18, 1006\u20131017 (2016).","journal-title":"Nat Cell Biol"},{"key":"47827_CR27","unstructured":"Zhang, Y. et al. Cooperative repression of IGF2R translation by miR-195 and RNA-binding protein CUGBP1. Mol Cell Biol (2017)."},{"key":"47827_CR28","doi-asserted-by":"publisher","first-page":"24408","DOI":"10.1074\/jbc.274.34.24408","volume":"274","author":"JC Byrd","year":"1999","unstructured":"Byrd, J. C., Devi, G. R., de Souza, A. T., Jirtle, R. L. & MacDonald, R. G. Disruption of ligand binding to the insulin-like growth factor II\/mannose 6-phosphate receptor by cancer-associated missense mutations. J Biol Chem 274, 24408\u201324416 (1999).","journal-title":"J Biol Chem"},{"key":"47827_CR29","doi-asserted-by":"publisher","first-page":"464","DOI":"10.1038\/372464a0","volume":"372","author":"ZQ Wang","year":"1994","unstructured":"Wang, Z. Q., Fung, M. R., Barlow, D. P. & Wagner, E. F. Regulation of embryonic growth and lysosomal targeting by the imprinted Igf2\/Mpr gene. Nature 372, 464\u2013467 (1994).","journal-title":"Nature"},{"key":"47827_CR30","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1093\/cvr\/cvu269","volume":"105","author":"H Shen","year":"2015","unstructured":"Shen, H. et al. Extracardiac control of embryonic cardiomyocyte proliferation and ventricular wall expansion. Cardiovasc Res 105, 271\u2013278 (2015).","journal-title":"Cardiovasc Res"},{"key":"47827_CR31","unstructured":"Frago, S. et al. Directed evolution of selected IGF2R domain 11 loop residues generates an IGF2 super-antagonist. in submission (2013)."},{"key":"47827_CR32","doi-asserted-by":"crossref","first-page":"3819","DOI":"10.1242\/dev.128.19.3819","volume":"128","author":"JL Burns","year":"2001","unstructured":"Burns, J. L. & Hassan, A. B. Cell survival and proliferation are modified by insulin-like growth factor 2 between days 9 and 10 of mouse gestation. Development 128, 3819\u20133830 (2001).","journal-title":"Development"},{"key":"47827_CR33","doi-asserted-by":"publisher","first-page":"447","DOI":"10.1038\/ng1295-447","volume":"11","author":"AT De Souza","year":"1995","unstructured":"De Souza, A. T., Hankins, G. R., Washington, M. K., Orton, T. C. & Jirtle, R. L. M6P\/IGF2R gene is mutated in human hepatocellular carcinomas with loss of heterozygosity. Nat Genet 11, 447\u2013449 (1995).","journal-title":"Nat Genet"},{"key":"47827_CR34","first-page":"4314","volume":"59","author":"GR Devi","year":"1999","unstructured":"Devi, G. R., De Souza, A. T., Byrd, J. C., Jirtle, R. L. & MacDonald, R. G. Altered ligand binding by insulin-like growth factor II\/mannose 6-phosphate receptors bearing missense mutations in human cancers. Cancer Res 59, 4314\u20134319 (1999).","journal-title":"Cancer Res"},{"key":"47827_CR35","first-page":"2003","volume":"12","author":"GR Hankins","year":"1996","unstructured":"Hankins, G. R. et al. M6P\/IGF2 receptor: a candidate breast tumor suppressor gene. Oncogene 12, 2003\u20132009 (1996).","journal-title":"Oncogene"},{"key":"47827_CR36","doi-asserted-by":"publisher","first-page":"1572","DOI":"10.1038\/sj.onc.1203437","volume":"19","author":"FM Kong","year":"2000","unstructured":"Kong, F. M., Anscher, M. S., Washington, M. K., Killian, J. K. & Jirtle, R. L. M6P\/IGF2R is mutated in squamous cell carcinoma of the lung. Oncogene 19, 1572\u20131578 (2000).","journal-title":"Oncogene"},{"key":"47827_CR37","doi-asserted-by":"publisher","first-page":"69883","DOI":"10.18632\/oncotarget.11513","volume":"7","author":"J Matheson","year":"2016","unstructured":"Matheson, J. et al. Epithelial-mesenchymal transition and nuclear beta-catenin induced by conditional intestinal disruption of Cdh1 with Apc is E-cadherin EC1 domain dependent. Oncotarget 7, 69883\u201369902 (2016).","journal-title":"Oncotarget"},{"key":"47827_CR38","doi-asserted-by":"publisher","first-page":"e26891","DOI":"10.1371\/journal.pone.0026891","volume":"6","author":"AF Bokov","year":"2011","unstructured":"Bokov, A. F. et al. Does reduced IGF-1R signaling in Igf1r+\/1 mice alter aging? PLoS One 6, e26891 (2011).","journal-title":"PLoS One"},{"key":"47827_CR39","doi-asserted-by":"publisher","first-page":"182","DOI":"10.1038\/nature01298","volume":"421","author":"M Holzenberger","year":"2003","unstructured":"Holzenberger, M. et al. IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice. Nature 421, 182\u2013187 (2003).","journal-title":"Nature"},{"key":"47827_CR40","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1016\/j.cmet.2011.07.001","volume":"14","author":"C Jin","year":"2011","unstructured":"Jin, C. et al. Histone demethylase UTX-1 regulates C. elegans life span by targeting the insulin\/IGF-1 signaling pathway. Cell Metab 14, 161\u2013172 (2011).","journal-title":"Cell Metab"},{"key":"47827_CR41","doi-asserted-by":"publisher","first-page":"174","DOI":"10.1111\/j.1474-9726.2010.00547.x","volume":"9","author":"M Pehar","year":"2010","unstructured":"Pehar, M. et al. Altered longevity-assurance activity of p53:p44 in the mouse causes memory loss, neurodegeneration and premature death. Aging Cell 9, 174\u2013190 (2010).","journal-title":"Aging Cell"},{"key":"47827_CR42","first-page":"429","volume":"68","author":"RM Adkins","year":"2010","unstructured":"Adkins, R. M. et al. Association of birth weight with polymorphisms in the IGF2, H19, and IGF2R genes. Pediatr Res 68, 429\u2013434 (2010).","journal-title":"Pediatr Res"},{"key":"47827_CR43","doi-asserted-by":"publisher","DOI":"10.1186\/1755-8794-3-9","volume":"3","author":"M Biong","year":"2010","unstructured":"Biong, M. et al. Genotypes and haplotypes in the insulin-like growth factors, their receptors and binding proteins in relation to plasma metabolic levels and mammographic density. BMC Med Genomics 3, 9 (2010).","journal-title":"BMC Med Genomics"},{"key":"47827_CR44","doi-asserted-by":"publisher","first-page":"1922","DOI":"10.1158\/1055-9965.EPI-09-0253","volume":"18","author":"I Cheng","year":"2009","unstructured":"Cheng, I. et al. IGF2R missense single-nucleotide polymorphisms and breast cancer risk: the multiethnic cohort study. Cancer Epidemiol Biomarkers Prev 18, 1922\u20131924 (2009).","journal-title":"Cancer Epidemiol Biomarkers Prev"},{"key":"47827_CR45","doi-asserted-by":"publisher","first-page":"206","DOI":"10.1016\/j.canep.2011.05.013","volume":"36","author":"X Dong","year":"2012","unstructured":"Dong, X. et al. Insulin-like growth factor axis gene polymorphisms modify risk of pancreatic cancer. Cancer Epidemiol 36, 206\u2013211 (2012).","journal-title":"Cancer Epidemiol"},{"key":"47827_CR46","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1002\/humu.1146","volume":"18","author":"JK Killian","year":"2001","unstructured":"Killian, J. K. et al. Mannose 6-phosphate\/insulin-like growth factor 2 receptor (M6P\/IGF2R) variants in American and Japanese populations. Hum Mutat 18, 25\u201331 (2001).","journal-title":"Hum Mutat"},{"key":"47827_CR47","doi-asserted-by":"publisher","first-page":"363","DOI":"10.1016\/j.ghir.2005.07.003","volume":"15","author":"CJ Petry","year":"2005","unstructured":"Petry, C. J. et al. Genetic variation in the type 2 insulin-like growth factor receptor gene and disparity in childhood height. Growth Horm IGF Res 15, 363\u2013368 (2005).","journal-title":"Growth Horm IGF Res"},{"key":"47827_CR48","doi-asserted-by":"publisher","first-page":"341","DOI":"10.1677\/JME-08-0154","volume":"42","author":"D Rezgui","year":"2009","unstructured":"Rezgui, D. et al. Structure and function of the human Gly1619Arg polymorphism of M6P\/IGF2R domain 11 implicated in IGF2 dependent growth. J Mol Endocrinol 42, 341\u2013356 (2009).","journal-title":"J Mol Endocrinol"},{"key":"47827_CR49","doi-asserted-by":"publisher","first-page":"1667","DOI":"10.1158\/1055-9965.EPI-07-0214","volume":"16","author":"SA Savage","year":"2007","unstructured":"Savage, S. A. et al. Analysis of genes critical for growth regulation identifies Insulin-like Growth Factor 2 Receptor variations with possible functional significance as risk factors for osteosarcoma. Cancer Epidemiol Biomarkers Prev 16, 1667\u20131674 (2007).","journal-title":"Cancer Epidemiol Biomarkers Prev"},{"key":"47827_CR50","doi-asserted-by":"publisher","first-page":"5057","DOI":"10.1113\/JP273330","volume":"595","author":"AN Sferruzzi-Perri","year":"2017","unstructured":"Sferruzzi-Perri, A. N., Sandovici, I., Constancia, M. & Fowden, A. L. Placental phenotype and the insulin-like growth factors: resource allocation to fetal growth. J Physiol 595, 5057\u20135093 (2017).","journal-title":"J Physiol"},{"key":"47827_CR51","doi-asserted-by":"publisher","first-page":"5279","DOI":"10.1073\/pnas.080409297","volume":"97","author":"V Grandjean","year":"2000","unstructured":"Grandjean, V., Smith, J., Schofield, P. N. & Ferguson-Smith, A. C. Increased IGF-II protein affects p57kip2 expression in vivo and in vitro: implications for Beckwith-Wiedemann syndrome. Proc Natl Acad Sci USA 97, 5279\u20135284 (2000).","journal-title":"Proc Natl Acad Sci USA"},{"key":"47827_CR52","doi-asserted-by":"publisher","first-page":"635","DOI":"10.1016\/S0959-8049(02)00627-5","volume":"39","author":"ML Berthe","year":"2003","unstructured":"Berthe, M. L. et al. Mannose-6-phosphate\/insulin-like growth factor-II receptor expression levels during the progression from normal human mammary tissue to invasive breast carcinomas. Eur J Cancer 39, 635\u2013642 (2003).","journal-title":"Eur J Cancer"},{"key":"47827_CR53","first-page":"2542","volume":"133","author":"NJ Caixeiro","year":"2013","unstructured":"Caixeiro, N. J., Martin, J. L. & Scott, C. D. Silencing the mannose 6-phosphate\/IGF-II receptor differentially affects tumorigenic properties of normal breast epithelial cells. Int J Cancer 133, 2542\u20132550 (2013).","journal-title":"Int J Cancer"},{"key":"47827_CR54","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2407-2-18","volume":"2","author":"Z Chen","year":"2002","unstructured":"Chen, Z., Ge, Y., Landman, N. & Kang, J. X. Decreased expression of the mannose 6-phosphate\/insulin-like growth factor-II receptor promotes growth of human breast cancer cells. BMC Cancer 2, 18 (2002).","journal-title":"BMC Cancer"},{"key":"47827_CR55","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1007\/s10540-006-9002-3","volume":"26","author":"E Hebert","year":"2006","unstructured":"Hebert, E. Mannose-6-phosphate\/insulin-like growth factor II receptor expression and tumor development. Biosci Rep 26, 7\u201317 (2006).","journal-title":"Biosci Rep"},{"key":"47827_CR56","doi-asserted-by":"publisher","first-page":"870","DOI":"10.1667\/RR0585.1","volume":"166","author":"KS Iwamoto","year":"2006","unstructured":"Iwamoto, K. S., Yano, S., Barber, C. L., MacPhee, D. G. & Tokuoka, S. A dose-dependent decrease in the fraction of cases harboring M6P\/IGF2R mutations in hepatocellular carcinomas from the atomic bomb survivors. Radiat Res 166, 870\u2013876 (2006).","journal-title":"Radiat Res"},{"key":"47827_CR57","doi-asserted-by":"publisher","first-page":"2695","DOI":"10.1111\/j.1742-4658.2012.08652.x","volume":"279","author":"JL Kreiling","year":"2012","unstructured":"Kreiling, J. L. et al. Dominant-negative effect of truncated mannose 6-phosphate\/insulin-like growth factor II receptor species in cancer. FEBS J 279, 2695\u20132713 (2012).","journal-title":"FEBS J"},{"key":"47827_CR58","doi-asserted-by":"publisher","first-page":"1953","DOI":"10.1016\/S0002-9440(10)61144-3","volume":"160","author":"SA Kuismanen","year":"2002","unstructured":"Kuismanen, S. A. et al. Endometrial and colorectal tumors from patients with hereditary nonpolyposis colon cancer display different patterns of microsatellite instability. Am J Pathol 160, 1953\u20131958 (2002).","journal-title":"Am J Pathol"},{"key":"47827_CR59","doi-asserted-by":"publisher","first-page":"305","DOI":"10.1007\/978-0-387-69080-3_28","volume":"617","author":"GJ Lemamy","year":"2008","unstructured":"Lemamy, G. J., Sahla, M. E., Berthe, M. L. & Roger, P. Is the mannose-6-phosphate\/insulin-like growth factor 2 receptor coded by a breast cancer suppressor gene? Adv Exp Med Biol 617, 305\u2013310 (2008).","journal-title":"Adv Exp Med Biol"},{"key":"47827_CR60","doi-asserted-by":"publisher","first-page":"9359","DOI":"10.1038\/sj.onc.1208039","volume":"23","author":"J Li","year":"2004","unstructured":"Li, J. & Sahagian, G. G. Demonstration of tumor suppression by mannose 6-phosphate\/insulin-like growth factor 2 receptor. Oncogene 23, 9359\u20139368 (2004).","journal-title":"Oncogene"},{"key":"47827_CR61","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1016\/j.canlet.2009.06.036","volume":"289","author":"I Martin-Kleiner","year":"2010","unstructured":"Martin-Kleiner, I. & Gall Troselj, K. Mannose-6-phosphate\/insulin-like growth factor 2 receptor (M6P\/IGF2R) in carcinogenesis. Cancer Lett 289, 11\u201322 (2010).","journal-title":"Cancer Lett"},{"key":"47827_CR62","doi-asserted-by":"publisher","first-page":"4287","DOI":"10.1210\/en.2002-220548","volume":"143","author":"DB O\u2019Gorman","year":"2002","unstructured":"O\u2019Gorman, D. B., Weiss, J., Hettiaratchi, A., Firth, S. M. & Scott, C. D. Insulin-like growth factor-II\/mannose 6-phosphate receptor overexpression reduces growth of choriocarcinoma cells in vitro and in vivo. Endocrinology 143, 4287\u20134294 (2002).","journal-title":"Endocrinology"},{"key":"47827_CR63","doi-asserted-by":"publisher","first-page":"2559","DOI":"10.1002\/ijc.24236","volume":"124","author":"OC Probst","year":"2009","unstructured":"Probst, O. C. et al. The mannose 6-phosphate\/insulin-like growth factor II receptor restricts the tumourigenicity and invasiveness of squamous cell carcinoma cells. Int J Cancer 124, 2559\u20132567 (2009).","journal-title":"Int J Cancer"},{"key":"47827_CR64","doi-asserted-by":"publisher","first-page":"337","DOI":"10.1016\/j.jhep.2012.03.026","volume":"57","author":"V Puxbaum","year":"2012","unstructured":"Puxbaum, V. et al. M6P\/IGF2R modulates the invasiveness of liver cells via its capacity to bind mannose 6-phosphate residues. J Hepatol 57, 337\u2013343 (2012).","journal-title":"J Hepatol"},{"key":"47827_CR65","doi-asserted-by":"publisher","first-page":"1327","DOI":"10.1158\/0008-5472.CAN-05-3107","volume":"66","author":"TL Wise","year":"2006","unstructured":"Wise, T. L. & Pravtcheva, D. D. Delayed onset of Igf2-induced mammary tumors in Igf2r transgenic mice. Cancer Res 66, 1327\u20131336 (2006).","journal-title":"Cancer Res"},{"key":"47827_CR66","doi-asserted-by":"publisher","first-page":"414","DOI":"10.1038\/369414a0","volume":"369","author":"G Christofori","year":"1994","unstructured":"Christofori, G., Naik, P. & Hanahan, D. A second signal supplied by insulin-like growth factor II in oncogene-induced tumorigenesis. Nature 369, 414\u2013418 (1994).","journal-title":"Nature"},{"key":"47827_CR67","doi-asserted-by":"publisher","first-page":"330","DOI":"10.1038\/nature11252","volume":"487","author":"Cancer Genome Atlas, N.","year":"2012","unstructured":"Cancer Genome Atlas, N. Comprehensive molecular characterization of human colon and rectal cancer. Nature 487, 330\u2013337 (2012).","journal-title":"Nature"},{"key":"47827_CR68","doi-asserted-by":"publisher","first-page":"1243","DOI":"10.1107\/S0907444906029799","volume":"62","author":"AR Aricescu","year":"2006","unstructured":"Aricescu, A. R., Lu, W. & Jones, E. Y. A time- and cost-efficient system for high-level protein production in mammalian cells. Acta Crystallogr D Biol Crystallogr 62, 1243\u20131250 (2006).","journal-title":"Acta Crystallogr D Biol Crystallogr"},{"key":"47827_CR69","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1038\/345078a0","volume":"345","author":"TM DeChiara","year":"1990","unstructured":"DeChiara, T. M., Efstratiadis, A. & Robertson, E. J. A growth-deficiency phenotype in heterozygous mice carrying an insulin-like growth factor II gene disrupted by targeting. Nature 345, 78\u201380 (1990).","journal-title":"Nature"},{"key":"47827_CR70","doi-asserted-by":"publisher","first-page":"2868","DOI":"10.1073\/pnas.0500039102","volume":"102","author":"J Haines","year":"2005","unstructured":"Haines, J. et al. Genetic basis of variation in adenoma multiplicity in ApcMin\/+ Mom1S mice. Proc Natl Acad Sci USA 102, 2868\u20132873 (2005).","journal-title":"Proc Natl Acad Sci USA"},{"key":"47827_CR71","doi-asserted-by":"publisher","first-page":"120","DOI":"10.1126\/science.278.5335.120","volume":"278","author":"H Shibata","year":"1997","unstructured":"Shibata, H. et al. Rapid colorectal adenoma formation initiated by conditional targeting of the Apc gene. Science 278, 120\u2013123 (1997).","journal-title":"Science"},{"key":"47827_CR72","doi-asserted-by":"publisher","first-page":"186","DOI":"10.1002\/gene.20042","volume":"39","author":"F el Marjou","year":"2004","unstructured":"el Marjou, F. et al. Tissue-specific and inducible Cre-mediated recombination in the gut epithelium. Genesis 39, 186\u2013193 (2004).","journal-title":"Genesis"},{"key":"47827_CR73","doi-asserted-by":"publisher","first-page":"1003","DOI":"10.1038\/nature06196","volume":"449","author":"N Barker","year":"2007","unstructured":"Barker, N. et al. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449, 1003\u20131007 (2007).","journal-title":"Nature"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-47827-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-47827-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-47827-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,17]],"date-time":"2022-12-17T12:19:17Z","timestamp":1671279557000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-47827-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,8,6]]},"references-count":73,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2019,12]]}},"alternative-id":["47827"],"URL":"https:\/\/doi.org\/10.1038\/s41598-019-47827-9","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,8,6]]},"assertion":[{"value":"16 February 2018","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 July 2019","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 August 2019","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"11388"}}