{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T13:46:17Z","timestamp":1791812777777,"version":"4.3.4"},"reference-count":50,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2016,9,14]],"date-time":"2016-09-14T00:00:00Z","timestamp":1473811200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2016,9,14]],"date-time":"2016-09-14T00:00:00Z","timestamp":1473811200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Commun"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Adrenal cortex physiology relies on functional zonation, essential for production of aldosterone by outer zona glomerulosa (ZG) and glucocorticoids by inner zona fasciculata (ZF). The cortex undergoes constant cell renewal, involving recruitment of subcapsular progenitors to ZG fate and subsequent lineage conversion to ZF identity. Here we show that WNT4 is an important driver of WNT pathway activation and subsequent ZG differentiation and demonstrate that PKA activation prevents ZG differentiation through WNT4 repression and WNT pathway inhibition. This suggests that PKA activation in ZF is a key driver of WNT inhibition and lineage conversion. Furthermore, we provide evidence that constitutive PKA activation inhibits, whereas partial inactivation of PKA catalytic activity stimulates \u03b2-catenin-induced tumorigenesis. Together, both lower PKA activity and higher WNT pathway activity lead to poorer prognosis in adrenocortical carcinoma (ACC) patients. These observations suggest that PKA acts as a tumour suppressor in the adrenal cortex, through repression of WNT signalling.<\/jats:p>","DOI":"10.1038\/ncomms12751","type":"journal-article","created":{"date-parts":[[2016,9,14]],"date-time":"2016-09-14T09:29:59Z","timestamp":1473845399000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":134,"title":["PKA inhibits WNT signalling in adrenal cortex zonation and prevents malignant tumour development"],"prefix":"10.1038","volume":"7","author":[{"given":"Coralie","family":"Drelon","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annabel","family":"Berthon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabelle","family":"Sahut-Barnola","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Micka\u00ebl","family":"Mathieu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Typhanie","family":"Dumontet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"St\u00e9phanie","family":"Rodriguez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Batisse-Lignier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Houda","family":"Tabbal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Igor","family":"Tauveron","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne-Marie","family":"Lefran\u00e7ois-Martinez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Christophe","family":"Pointud","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Celso E.","family":"Gomez-Sanchez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seppo","family":"Vainio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingdong","family":"Shan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonia","family":"Sacco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Schedl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Constantine A.","family":"Stratakis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antoine","family":"Martinez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre","family":"Val","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,9,14]]},"reference":[{"key":"BFncomms12751_CR1","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1210\/er.2008-0039","volume":"30","author":"AC Kim","year":"2009","unstructured":"Kim, A. C. et al. In search of adrenocortical stem and progenitor cells. Endocr. Rev. 30, 241\u2013263 (2009).","journal-title":"Endocr. Rev."},{"key":"BFncomms12751_CR2","doi-asserted-by":"publisher","first-page":"156","DOI":"10.1016\/j.mce.2014.12.014","volume":"408","author":"C Drelon","year":"2015","unstructured":"Drelon, C., Berthon, A., Mathieu, M., Martinez, A. & Val, P. Adrenal cortex tissue homeostasis and zonation: a WNT perspective. Mol. Cell. Endocrinol. 408, 156\u2013164 (2015).","journal-title":"Mol. Cell. Endocrinol."},{"key":"BFncomms12751_CR3","doi-asserted-by":"publisher","first-page":"21185","DOI":"10.1073\/pnas.0909471106","volume":"106","author":"P King","year":"2009","unstructured":"King, P., Paul, A. & Laufer, E. Shh signalling regulates adrenocortical development and identifies progenitors of steroidogenic lineages. Proc. Natl Acad. Sci. USA 106, 21185\u201321190 (2009).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"BFncomms12751_CR4","doi-asserted-by":"publisher","first-page":"666","DOI":"10.1016\/j.devcel.2013.07.016","volume":"26","author":"BD Freedman","year":"2013","unstructured":"Freedman, B. D. et al. Adrenocortical zonation results from lineage conversion of differentiated zona glomerulosa cells. Dev. Cell 26, 666\u2013673 (2013).","journal-title":"Dev. Cell"},{"key":"BFncomms12751_CR5","doi-asserted-by":"publisher","first-page":"759","DOI":"10.1016\/j.devcel.2006.03.015","volume":"10","author":"S Benhamouche","year":"2006","unstructured":"Benhamouche, S. et al. Apc tumour suppressor gene is the \u2018zonation-keeper\u2019 of mouse liver. Dev Cell 10, 759\u2013770 (2006).","journal-title":"Dev Cell"},{"key":"BFncomms12751_CR6","doi-asserted-by":"publisher","first-page":"1561","DOI":"10.1093\/hmg\/ddq029","volume":"19","author":"A Berthon","year":"2010","unstructured":"Berthon, A. et al. Constitutive {beta}-catenin activation induces adrenal hyperplasia and promotes adrenal cancer development. Hum. Mol. Genet. 19, 1561\u20131576 (2010).","journal-title":"Hum. Mol. Genet."},{"key":"BFncomms12751_CR7","doi-asserted-by":"publisher","first-page":"889","DOI":"10.1093\/hmg\/ddt484","volume":"23","author":"A Berthon","year":"2014","unstructured":"Berthon, A. et al. WNT\/\u03b2-catenin signalling is activated in aldosterone-producing adenomas and controls aldosterone production. Hum. Mol. Genet 23, 889\u2013905 (2014).","journal-title":"Hum. Mol. Genet"},{"key":"BFncomms12751_CR8","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1530\/JME-11-0011","volume":"46","author":"RJ Gorrigan","year":"2011","unstructured":"Gorrigan, R. J., Guasti, L., King, P., Clark, A. J. & Chan, L. F. Localisation of the melanocortin-2-receptor and its accessory proteins in the developing and adult adrenal gland. J. Mol. Endocrinol. 46, 227\u2013232 (2011).","journal-title":"J. Mol. Endocrinol."},{"key":"BFncomms12751_CR9","doi-asserted-by":"publisher","first-page":"18205","DOI":"10.1073\/pnas.0706953104","volume":"104","author":"D Chida","year":"2007","unstructured":"Chida, D. et al. Melanocortin 2 receptor is required for adrenal gland development, steroidogenesis, and neonatal gluconeogenesis. Proc. Natl Acad. Sci. USA 104, 18205\u201318210 (2007).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"BFncomms12751_CR10","doi-asserted-by":"publisher","first-page":"1471","DOI":"10.1210\/me.2014-1060","volume":"28","author":"EM Walczak","year":"2014","unstructured":"Walczak, E. M. et al. Wnt-signalling inhibits adrenal steroidogenesis by cell-autonomous and non-cell-autonomous mechanisms. Mol. Endocrinol. 28, 1471\u20131486 (2014).","journal-title":"Mol. Endocrinol."},{"key":"BFncomms12751_CR11","first-page":"93","volume":"15","author":"C Aigueperse","year":"2001","unstructured":"Aigueperse, C. et al. SF-1 (steroidogenic factor-1), C\/EBPbeta (CCAAT\/enhancer binding protein), and ubiquitous transcription factors NF1 (nuclear factor 1) and Sp1 (selective promoter factor 1) are required for regulation of the mouse aldose reductase-like gene (AKR1B7) expression in adrenocortical cells. Mol. Endocrinol. 15, 93\u2013111 (2001).","journal-title":"Mol. Endocrinol."},{"key":"BFncomms12751_CR12","doi-asserted-by":"crossref","first-page":"4557","DOI":"10.1242\/dev.126.20.4557","volume":"126","author":"R DasGupta","year":"1999","unstructured":"DasGupta, R. & Fuchs, E. Multiple roles for activated LEF\/TCF transcription complexes during hair follicle development and differentiation. Development 126, 4557\u20134568 (1999).","journal-title":"Development"},{"key":"BFncomms12751_CR13","doi-asserted-by":"publisher","first-page":"4506","DOI":"10.1158\/0008-5472.CAN-05-0580","volume":"65","author":"LS Kirschner","year":"2005","unstructured":"Kirschner, L. S. et al. A mouse model for the Carney complex tumour syndrome develops neoplasia in cyclic AMP-responsive tissues. Cancer Res. 65, 4506\u20134514 (2005).","journal-title":"Cancer Res."},{"key":"BFncomms12751_CR14","doi-asserted-by":"publisher","first-page":"419","DOI":"10.1002\/dvg.20231","volume":"44","author":"NC Bingham","year":"2006","unstructured":"Bingham, N. C., Verma-Kurvari, S., Parada, L. F. & Parker, K. L. Development of a steroidogenic factor 1\/Cre transgenic mouse line. Genesis 44, 419\u2013424 (2006).","journal-title":"Genesis"},{"key":"BFncomms12751_CR15","doi-asserted-by":"publisher","first-page":"593","DOI":"10.1002\/dvg.20335","volume":"45","author":"MD Muzumdar","year":"2007","unstructured":"Muzumdar, M. D., Tasic, B., Miyamichi, K., Li, L. & Luo, L. A global double-fluorescent Cre reporter mouse. Genesis 45, 593\u2013605 (2007).","journal-title":"Genesis"},{"key":"BFncomms12751_CR16","doi-asserted-by":"publisher","first-page":"e1000980","DOI":"10.1371\/journal.pgen.1000980","volume":"6","author":"I Sahut-Barnola","year":"2010","unstructured":"Sahut-Barnola, I. et al. Cushing\u2019s syndrome and foetal features resurgence in adrenal cortex-specific Prkar1a knockout mice. PLoS Genet. 6, e1000980 (2010).","journal-title":"PLoS Genet."},{"key":"BFncomms12751_CR17","doi-asserted-by":"publisher","first-page":"11960","DOI":"10.1073\/pnas.220413597","volume":"97","author":"X Fang","year":"2000","unstructured":"Fang, X. et al. Phosphorylation and inactivation of glycogen synthase kinase 3 by protein kinase A. Proc. Natl Acad. Sci. USA 97, 11960\u201311965 (2000).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"BFncomms12751_CR18","doi-asserted-by":"publisher","first-page":"9971","DOI":"10.1074\/jbc.M508778200","volume":"281","author":"S Taurin","year":"2006","unstructured":"Taurin, S., Sandbo, N., Qin, Y., Browning, D. & Dulin, N. O. Phosphorylation of beta-catenin by cyclic AMP-dependent protein kinase. J. Biol. Chem. 281, 9971\u20139976 (2006).","journal-title":"J. Biol. Chem."},{"key":"BFncomms12751_CR19","doi-asserted-by":"publisher","first-page":"9063","DOI":"10.1128\/MCB.25.20.9063-9072.2005","volume":"25","author":"S Hino","year":"2005","unstructured":"Hino, S., Tanji, C., Nakayama, K. I. & Kikuchi, A. Phosphorylation of beta-catenin by cyclic AMP-dependent protein kinase stabilizes beta-catenin through inhibition of its ubiquitination. Mol. Cell. Biol. 25, 9063\u20139072 (2005).","journal-title":"Mol. Cell. Biol."},{"key":"BFncomms12751_CR20","doi-asserted-by":"publisher","first-page":"e109523","DOI":"10.1371\/journal.pone.0109523","volume":"9","author":"M Zhang","year":"2014","unstructured":"Zhang, M. et al. Protein kinase A activation enhances \u03b2-catenin transcriptional activity through nuclear localization to PML bodies. PLoS ONE 9, e109523 (2014).","journal-title":"PLoS ONE"},{"key":"BFncomms12751_CR21","doi-asserted-by":"publisher","first-page":"803","DOI":"10.1002\/j.1460-2075.1993.tb05715.x","volume":"12","author":"K Hughes","year":"1993","unstructured":"Hughes, K., Nikolakaki, E., Plyte, S. E., Totty, N. F. & Woodgett, J. R. Modulation of the glycogen synthase kinase-3 family by tyrosine phosphorylation. EMBO J. 12, 803\u2013808 (1993).","journal-title":"EMBO J."},{"key":"BFncomms12751_CR22","doi-asserted-by":"publisher","first-page":"2690","DOI":"10.1016\/j.yexcr.2009.06.021","volume":"315","author":"A Railo","year":"2009","unstructured":"Railo, A. et al. Genomic response to Wnt signalling is highly context-dependent\u2014evidence from DNA microarray and chromatin immunoprecipitation screens of Wnt\/TCF targets. Exp. Cell Res. 315, 2690\u20132704 (2009).","journal-title":"Exp. Cell Res."},{"key":"BFncomms12751_CR23","doi-asserted-by":"publisher","first-page":"665","DOI":"10.1038\/nature11308","volume":"488","author":"B-K Koo","year":"2012","unstructured":"Koo, B.-K. et al. Tumour suppressor RNF43 is a stem-cell E3 ligase that induces endocytosis of Wnt receptors. Nature 488, 665\u2013669 (2012).","journal-title":"Nature"},{"key":"BFncomms12751_CR24","doi-asserted-by":"publisher","first-page":"3116","DOI":"10.1242\/jcs.147835","volume":"127","author":"R Jin","year":"2014","unstructured":"Jin, R. et al. The metastasis suppressor NDRG1 modulates the phosphorylation and nuclear translocation of \u03b2-catenin through mechanisms involving FRAT1 and PAK4. J. Cell Sci. 127, 3116\u20133130 (2014).","journal-title":"J. Cell Sci."},{"key":"BFncomms12751_CR25","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1016\/j.cell.2006.01.053","volume":"125","author":"C Mosimann","year":"2006","unstructured":"Mosimann, C., Hausmann, G. & Basler, K. Parafibromin\/Hyrax activates Wnt\/Wg target gene transcription by direct association with beta-catenin\/Armadillo. Cell 125, 327\u2013341 (2006).","journal-title":"Cell"},{"key":"BFncomms12751_CR26","doi-asserted-by":"publisher","first-page":"ra25","DOI":"10.1126\/scisignal.2000230","volume":"2","author":"RG James","year":"2009","unstructured":"James, R. G. et al. Bruton\u2019s tyrosine kinase revealed as a negative regulator of Wnt-beta-catenin signalling. Sci. Signal. 2, ra25 (2009).","journal-title":"Sci. Signal."},{"key":"BFncomms12751_CR27","doi-asserted-by":"publisher","first-page":"4358","DOI":"10.1210\/en.2002-220275","volume":"143","author":"M Heikkila","year":"2002","unstructured":"Heikkila, M. et al. Wnt-4 deficiency alters mouse adrenal cortex function, reducing aldosterone production. Endocrinology 143, 4358\u20134365 (2002).","journal-title":"Endocrinology"},{"key":"BFncomms12751_CR28","doi-asserted-by":"publisher","first-page":"549","DOI":"10.1055\/s-2006-950500","volume":"38","author":"M Chen","year":"2006","unstructured":"Chen, M. & Hornsby, P. J. Adenovirus-delivered DKK3\/WNT4 and steroidogenesis in primary cultures of adrenocortical cells. Horm. Metab. Res. 38, 549\u2013555 (2006).","journal-title":"Horm. Metab. Res."},{"key":"BFncomms12751_CR29","doi-asserted-by":"publisher","first-page":"782","DOI":"10.1002\/dvg.20566","volume":"47","author":"J Shan","year":"2009","unstructured":"Shan, J., Jokela, T., Peltoketo, H. & Vainio, S. Generation of an allele to inactivate Wnt4 gene function conditionally in the mouse. Genesis 47, 782\u2013788 (2009).","journal-title":"Genesis"},{"key":"BFncomms12751_CR30","doi-asserted-by":"publisher","first-page":"5931","DOI":"10.1093\/emboj\/18.21.5931","volume":"18","author":"N Harada","year":"1999","unstructured":"Harada, N. et al. Intestinal polyposis in mice with a dominant stable mutation of the beta-catenin gene. EMBO J. 18, 5931\u20135942 (1999).","journal-title":"EMBO J."},{"key":"BFncomms12751_CR31","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1016\/j.mce.2012.04.004","volume":"361","author":"C-CJ Huang","year":"2012","unstructured":"Huang, C.-C. J., Liu, C. & Yao, H. H.-C. Investigating the role of adrenal cortex in organization and differentiation of the adrenal medulla in mice. Mol. Cell. Endocrinol. 361, 165\u2013171 (2012).","journal-title":"Mol. Cell. Endocrinol."},{"key":"BFncomms12751_CR32","doi-asserted-by":"publisher","first-page":"2644","DOI":"10.1210\/en.2006-1509","volume":"148","author":"DG Romero","year":"2007","unstructured":"Romero, D. G. et al. Disabled-2 is expressed in adrenal zona glomerulosa and is involved in aldosterone secretion. Endocrinology 148, 2644\u20132652 (2007).","journal-title":"Endocrinology"},{"key":"BFncomms12751_CR33","doi-asserted-by":"publisher","first-page":"723","DOI":"10.1016\/j.ccell.2016.04.002","volume":"29","author":"S Zheng","year":"2016","unstructured":"Zheng, S. et al. Comprehensive pan-genomic characterization of adrenocortical carcinoma. Cancer Cell 29, 723\u2013736 (2016).","journal-title":"Cancer Cell"},{"key":"BFncomms12751_CR34","doi-asserted-by":"publisher","first-page":"1389","DOI":"10.1101\/gad.277756.116","volume":"30","author":"V Vidal","year":"2016","unstructured":"Vidal, V. et al. The adrenal capsule is a signalling centre controlling cell renewal and zonation through Rspo3. Genes Dev. 30, 1389\u20131394 (2016).","journal-title":"Genes Dev."},{"key":"BFncomms12751_CR35","doi-asserted-by":"publisher","first-page":"19889","DOI":"10.1074\/jbc.M111412200","volume":"277","author":"Y Huang","year":"2002","unstructured":"Huang, Y., Roelink, H. & McKnight, G. S. Protein kinase A deficiency causes axially localized neural tube defects in mice. J. Biol. Chem. 277, 19889\u201319896 (2002).","journal-title":"J. Biol. Chem."},{"key":"BFncomms12751_CR36","doi-asserted-by":"publisher","first-page":"367","DOI":"10.1111\/j.1365-2265.2008.03273.x","volume":"69","author":"M Tadjine","year":"2008","unstructured":"Tadjine, M. et al. Detection of somatic beta-catenin mutations in primary pigmented nodular adrenocortical disease. Clin. Endocrinol. (Oxf) 69, 367\u2013373 (2008).","journal-title":"Clin. Endocrinol. (Oxf)"},{"key":"BFncomms12751_CR37","doi-asserted-by":"publisher","first-page":"E687","DOI":"10.1210\/jc.2011-3000","volume":"97","author":"MQ Almeida","year":"2012","unstructured":"Almeida, M. Q. et al. Activation of cyclic AMP signalling leads to different pathway alterations in lesions of the adrenal cortex caused by germline PRKAR1A defects versus those due to somatic GNAS mutations. J. Clin. Endocrinol. Metab. 97, E687\u2013E693 (2012).","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"BFncomms12751_CR38","doi-asserted-by":"publisher","first-page":"4135","DOI":"10.1210\/jc.2008-0631","volume":"93","author":"S Gaujoux","year":"2008","unstructured":"Gaujoux, S. et al. Wnt\/beta-catenin and 3\u2019,5\u2019-cyclic adenosine 5\u2019-monophosphate\/protein kinase A signalling pathways alterations and somatic beta-catenin gene mutations in the progression of adrenocortical tumours. J. Clin. Endocrinol. Metab. 93, 4135\u20134140 (2008).","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"BFncomms12751_CR39","doi-asserted-by":"publisher","first-page":"2","DOI":"10.4158\/EP10412.RA","volume":"17","author":"MF Azevedo","year":"2011","unstructured":"Azevedo, M. F. & Stratakis, C. A. The transcriptome that mediates increased cAMP signalling in PRKAR1A defects and other settings. Endocr. Pract. 17, 2\u20137 (2011).","journal-title":"Endocr. Pract."},{"key":"BFncomms12751_CR40","doi-asserted-by":"publisher","first-page":"584","DOI":"10.1210\/jc.2005-1301","volume":"91","author":"A Horvath","year":"2006","unstructured":"Horvath, A. et al. Serial analysis of gene expression in adrenocortical hyperplasia caused by a germline PRKAR1A mutation. J. Clin. Endocrinol. Metab. 91, 584\u2013596 (2006).","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"BFncomms12751_CR41","doi-asserted-by":"publisher","first-page":"e44171","DOI":"10.1371\/journal.pone.0044171","volume":"7","author":"C Drelon","year":"2012","unstructured":"Drelon, C. et al. Analysis of the role of Igf2 in adrenal tumour development in transgenic mouse models. PLoS ONE 7, e44171 (2012).","journal-title":"PLoS ONE"},{"key":"BFncomms12751_CR42","first-page":"3054","volume":"82","author":"M Reincke","year":"1997","unstructured":"Reincke, M. et al. Deletion of the adrenocorticotropin receptor gene in human adrenocortical tumours: implications for tumorigenesis. J. Clin. Endocrinol. Metab. 82, 3054\u20133058 (1997).","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"BFncomms12751_CR43","doi-asserted-by":"publisher","first-page":"793","DOI":"10.1038\/ncb3164","volume":"17","author":"R Iglesias-Bartolome","year":"2015","unstructured":"Iglesias-Bartolome, R. et al. Inactivation of a G\u03b1s-PKA tumour suppressor pathway in skin stem cells initiates basal-cell carcinogenesis. Nat. Cell Biol. 17, 793\u2013803 (2015).","journal-title":"Nat. Cell Biol."},{"key":"BFncomms12751_CR44","doi-asserted-by":"publisher","first-page":"7622","DOI":"10.1158\/0008-5472.CAN-05-0593","volume":"65","author":"F Tissier","year":"2005","unstructured":"Tissier, F. et al. Mutations of beta-catenin in adrenocortical tumours: activation of the Wnt signalling pathway is a frequent event in both benign and malignant adrenocortical tumours. Cancer Res. 65, 7622\u20137627 (2005).","journal-title":"Cancer Res."},{"key":"BFncomms12751_CR45","doi-asserted-by":"publisher","first-page":"3149","DOI":"10.1038\/ncomms4149","volume":"5","author":"C Wu","year":"2014","unstructured":"Wu, C. et al. RSPO2-LGR5 signalling has tumour-suppressive activity in colorectal cancer. Nat. Commun 5, 3149 (2014).","journal-title":"Nat. Commun"},{"key":"BFncomms12751_CR46","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1038\/ng1330","volume":"36","author":"H Suzuki","year":"2004","unstructured":"Suzuki, H. et al. Epigenetic inactivation of SFRP genes allows constitutive WNT signalling in colorectal cancer. Nat. Genet. 36, 417\u2013422 (2004).","journal-title":"Nat. Genet."},{"key":"BFncomms12751_CR47","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1016\/j.molcel.2011.05.014","volume":"43","author":"A Takahashi","year":"2011","unstructured":"Takahashi, A. et al. SHP2 tyrosine phosphatase converts parafibromin\/Cdc73 from a tumour suppressor to an oncogenic driver. Mol. Cell 43, 45\u201356 (2011).","journal-title":"Mol. Cell"},{"key":"BFncomms12751_CR48","doi-asserted-by":"publisher","first-page":"655","DOI":"10.1038\/msb.2013.12","volume":"9","author":"RH Newman","year":"2013","unstructured":"Newman, R. H. et al. Construction of human activity-based phosphorylation networks. Mol. Syst. Biol. 9, 655 (2013).","journal-title":"Mol. Syst. Biol."},{"key":"BFncomms12751_CR49","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1016\/j.mce.2008.10.045","volume":"300","author":"S Lambert-Langlais","year":"2009","unstructured":"Lambert-Langlais, S. et al. A transgenic mouse line with specific Cre recombinase expression in the adrenal cortex. Mol. Cell. Endocrinol. 300, 197\u2013204 (2009).","journal-title":"Mol. Cell. Endocrinol."},{"key":"BFncomms12751_CR50","first-page":"630","volume":"16","author":"BS Sk\u00e5lhegg","year":"2002","unstructured":"Sk\u00e5lhegg, B. S. et al. Mutation of the Calpha subunit of PKA leads to growth retardation and sperm dysfunction. Mol. Endocrinol. 16, 630\u2013639 (2002).","journal-title":"Mol. Endocrinol."}],"container-title":["Nature Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/ncomms12751.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/ncomms12751","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/ncomms12751.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,4]],"date-time":"2023-01-04T10:12:07Z","timestamp":1672827127000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/ncomms12751"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,9,14]]},"references-count":50,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2016,11,25]]}},"alternative-id":["BFncomms12751"],"URL":"https:\/\/doi.org\/10.1038\/ncomms12751","relation":{},"ISSN":["2041-1723"],"issn-type":[{"value":"2041-1723","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,9,14]]},"assertion":[{"value":"30 July 2015","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 July 2016","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 September 2016","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"12751"}}