{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,12]],"date-time":"2025-12-12T13:23:54Z","timestamp":1765545834229},"reference-count":49,"publisher":"Portland Press Ltd.","issue":"2","content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2013,7,15]]},"abstract":"<jats:p>GH (growth hormone) binding to the GHR (GH receptor) triggers essential signalling pathways that promote growth and metabolic regulation. The sensitivity of the cells to GH is mainly controlled by the endocytosis of the receptor via \u03b2TrCP (\u03b2-transducin repeat-containing protein). In the present study, we show that \u03b2TrCP interacts directly via its WD40 domain with the UbE (ubiquitin-dependent endocytosis) motif in GHR, promoting GHR ubiquitination in\u00a0vitro. NMR experiments demonstrated that the UbE motif is essentially unstructured, and, together with functional mapping of the UbE and \u03b2TrCP WD40 residues necessary for binding, led to a unique interaction model of \u03b2TrCP with GHR\u2013UbE. This interaction is different from the conventional \u03b2TrCP\u2013substrate interactions described to date. This interaction therefore represents a promising specific target to develop drugs that inhibit GHR endocytosis and increase GH sensitivity in cachexia patients.<\/jats:p>","DOI":"10.1042\/bj20121843","type":"journal-article","created":{"date-parts":[[2013,4,23]],"date-time":"2013-04-23T09:34:49Z","timestamp":1366709689000},"page":"291-301","update-policy":"http:\/\/dx.doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["\u03b2TrCP interacts with the ubiquitin-dependent endocytosis motif of the GH receptor in an unconventional manner"],"prefix":"10.1042","volume":"453","author":[{"given":"Ana\u00a0C.","family":"da Silva Almeida","sequence":"first","affiliation":[{"name":"Department of Cell Biology and Institute of Biomembranes, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands"},{"name":"Drug Discovery Factory BV, Albrechtlaan 14-A, 1404 AK Bussum, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Henry G.","family":"Hocking","sequence":"additional","affiliation":[{"name":"Department of NMR Spectroscopy, Bijvoet Center for Biomolecular Research, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rolf","family":"Boelens","sequence":"additional","affiliation":[{"name":"Department of NMR Spectroscopy, Bijvoet Center for Biomolecular Research, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ger\u00a0J.","family":"Strous","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Institute of Biomembranes, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Agnes\u00a0G. S. H.","family":"van Rossum","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Institute of Biomembranes, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands"},{"name":"Drug Discovery Factory BV, Albrechtlaan 14-A, 1404 AK Bussum, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"288","published-online":{"date-parts":[[2013,6,28]]},"reference":[{"key":"2021112215411364600_B1","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1007\/s11154-007-9025-5","article-title":"Recent advances in growth hormone signaling","volume":"7","author":"Lanning","year":"2006","journal-title":"Rev. Endocr. Metab. Disord."},{"key":"2021112215411364600_B2","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/0092-8674(93)90415-M","article-title":"Identification of JAK2 as a growth hormone receptor-associated tyrosine kinase","volume":"74","author":"Argetsinger","year":"1993","journal-title":"Cell"},{"key":"2021112215411364600_B3","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1054\/ghir.2001.0237","article-title":"Growth hormone signalling and its regulation: preventing too much of a good thing","volume":"11","author":"Frank","year":"2001","journal-title":"Growth Horm. IGF Res."},{"key":"2021112215411364600_B4","doi-asserted-by":"crossref","first-page":"4533","DOI":"10.1210\/en.2007-0855","article-title":"Does growth hormone drive breast and other cancers?","volume":"148","author":"Waters","year":"2007","journal-title":"Endocrinology"},{"key":"2021112215411364600_B5","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1210\/er.2008-0022","article-title":"Growth hormone and insulin-like growth factor-I in the transition from normal mammary development to preneoplastic mammary lesions","volume":"30","author":"Kleinberg","year":"2009","journal-title":"Endocr. Rev."},{"key":"2021112215411364600_B6","doi-asserted-by":"crossref","first-page":"S9","DOI":"10.1016\/S1096-6374(00)80003-9","article-title":"Inflammatory cytokines and acquired growth hormone resistance","volume":"10","author":"von Laue","year":"2000","journal-title":"Growth Horm. IGF Res."},{"key":"2021112215411364600_B7","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1046\/j.1365-2265.2002.01540.x","article-title":"What is the role of the insulin-like growth factor system in the pathophysiology of cancer cachexia, and how is it regulated?","volume":"56","author":"Crown","year":"2002","journal-title":"Clin. Endocrinol."},{"key":"2021112215411364600_B8","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1016\/j.cytogfr.2006.09.006","article-title":"Waste management: cytokines, growth factors and cachexia","volume":"17","author":"Saini","year":"2006","journal-title":"Cytokine Growth Factor Rev."},{"key":"2021112215411364600_B9","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1152\/physrev.00016.2008","article-title":"Mechanisms of cancer cachexia","volume":"89","author":"Tisdale","year":"2009","journal-title":"Physiol. Rev."},{"key":"2021112215411364600_B10","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/S0303-7207(02)00258-7","article-title":"The ubiquitin\u2013proteasome pathway and the regulation of growth hormone receptor availability","volume":"197","author":"Strous","year":"2002","journal-title":"Mol. Cell. Endocrinol."},{"key":"2021112215411364600_B11","doi-asserted-by":"crossref","first-page":"3806","DOI":"10.1002\/j.1460-2075.1996.tb00754.x","article-title":"The ubiquitin conjugation system is required for ligand-induced endocytosis and degradation of the growth hormone receptor","volume":"15","author":"Strous","year":"1996","journal-title":"EMBO J."},{"key":"2021112215411364600_B12","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1093\/emboj\/18.1.28","article-title":"Identification of a novel ubiquitin conjugation motif, required for ligand-induced internalization of the growth hormone receptor","volume":"18","author":"Govers","year":"1999","journal-title":"EMBO J."},{"key":"2021112215411364600_B13","doi-asserted-by":"crossref","first-page":"20475","DOI":"10.1074\/jbc.M702610200","article-title":"The ubiquitin ligase SCF(\u03b2TrCP) regulates the degradation of the growth hormone receptor","volume":"282","author":"van Kerkhof","year":"2007","journal-title":"J. Biol. Chem."},{"key":"2021112215411364600_B14","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1146\/annurev.cellbio.15.1.435","article-title":"SCF and Cullin\/Ring H2-based ubiquitin ligases","volume":"15","author":"Deshaies","year":"1999","journal-title":"Annu. Rev. Cell Dev. Biol."},{"key":"2021112215411364600_B15","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1038\/nrm1547","article-title":"Function and regulation of cullin-RING ubiquitin ligases","volume":"6","author":"Petroski","year":"2005","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"2021112215411364600_B16","doi-asserted-by":"crossref","first-page":"5480","DOI":"10.1093\/emboj\/cdg524","article-title":"SCF(HOS) ubiquitin ligase mediates the ligand-induced down-regulation of the interferon-\u03b1 receptor","volume":"22","author":"Kumar","year":"2003","journal-title":"EMBO J."},{"key":"2021112215411364600_B17","doi-asserted-by":"crossref","first-page":"5215","DOI":"10.1182\/blood-2006-10-055350","article-title":"\u03b2-Trcp mediates ubiquitination and degradation of the erythropoietin receptor and controls cell proliferation","volume":"109","author":"Meyer","year":"2007","journal-title":"Blood"},{"key":"2021112215411364600_B18","doi-asserted-by":"crossref","first-page":"4038","DOI":"10.1128\/MCB.24.9.4038-4048.2004","article-title":"Negative regulation of prolactin receptor stability and signaling mediated by SCF(\u03b2-TrCP) E3 ubiquitin ligase","volume":"24","author":"Li","year":"2004","journal-title":"Mol. Cell. Biol."},{"key":"2021112215411364600_B19","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1210\/me.2011-1211","article-title":"\u03b2TrCP controls GH receptor degradation via two different motifs","volume":"26","author":"da Silva Almeida","year":"2012","journal-title":"Mol. Endocrinol."},{"key":"2021112215411364600_B20","doi-asserted-by":"crossref","first-page":"1445","DOI":"10.1016\/S1097-2765(03)00234-X","article-title":"Structure of a \u03b2-TrCP1\u2013Skp1\u2013\u03b2-catenin complex: destruction motif binding and lysine specificity of the SCF(\u03b2-TrCP1) ubiquitin ligase","volume":"11","author":"Wu","year":"2003","journal-title":"Mol. Cell"},{"key":"2021112215411364600_B21","doi-asserted-by":"crossref","first-page":"14741","DOI":"10.1021\/bi035207u","article-title":"NMR studies of the phosphorylation motif of the HIV-1 protein Vpu bound to the F-box protein \u03b2-TrCP","volume":"42","author":"Coadou","year":"2003","journal-title":"Biochemistry (Moscow)"},{"key":"2021112215411364600_B22","doi-asserted-by":"crossref","first-page":"29107","DOI":"10.1074\/jbc.M501628200","article-title":"STD and TRNOESY NMR studies on the conformation of the oncogenic protein \u03b2-catenin containing the phosphorylated motif DpSGXXpS bound to the \u03b2-TrCP protein","volume":"280","author":"Megy","year":"2005","journal-title":"J. Biol. Chem."},{"key":"2021112215411364600_B23","doi-asserted-by":"crossref","first-page":"2253","DOI":"10.1016\/j.peptides.2007.09.016","article-title":"Phosphorylation-dependent structure of ATF4 peptides derived from a human ATF4 protein, a member of the family of transcription factors","volume":"28","author":"Pons","year":"2007","journal-title":"Peptides"},{"key":"2021112215411364600_B24","doi-asserted-by":"crossref","first-page":"2958","DOI":"10.1021\/bi061401f","article-title":"Structural studies on 24P-I\u03baB\u03b1 peptide derived from a human I\u03baB\u03b1 protein related to the inhibition of the activity of the transcription factor NF-\u03baB","volume":"46","author":"Pons","year":"2007","journal-title":"Biochemistry (Moscow)"},{"key":"2021112215411364600_B25","doi-asserted-by":"crossref","first-page":"2350","DOI":"10.1021\/ci800248u","article-title":"Structure of the complex between phosphorylated substrates and the SCF \u03b2-TrCP ubiquitin ligase receptor: a combined NMR, molecular modeling, and docking approach","volume":"48","author":"Evrard-Todeschi","year":"2008","journal-title":"J. Chem. Inf. Model."},{"key":"2021112215411364600_B26","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1021\/bi7014212","article-title":"Transfer-NMR and docking studies identify the binding of the peptide derived from activating transcription factor 4 to protein ubiquitin ligase \u03b2-TrCP: competition STD-NMR with \u03b2-catenin","volume":"47","author":"Pons","year":"2008","journal-title":"Biochemistry (Moscow)"},{"key":"2021112215411364600_B27","doi-asserted-by":"crossref","first-page":"e14676","DOI":"10.1371\/journal.pone.0014676","article-title":"Jak2 is a negative regulator of ubiquitin-dependent endocytosis of the growth hormone receptor","volume":"6","author":"Putters","year":"2011","journal-title":"PLoS ONE"},{"key":"2021112215411364600_B28","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1002\/prot.20449","article-title":"The CCPN data model for NMR spectroscopy: development of a software pipeline","volume":"59","author":"Vranken","year":"2005","journal-title":"Proteins"},{"key":"2021112215411364600_B29","doi-asserted-by":"crossref","first-page":"1647","DOI":"10.1021\/bi00121a010","article-title":"The chemical shift index: a fast and simple method for the assignment of protein secondary structure through NMR spectroscopy","volume":"31","author":"Wishart","year":"1992","journal-title":"Biochemistry (Moscow)"},{"key":"2021112215411364600_B30","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/S0022-2836(02)00241-3","article-title":"Protein NMR structure determination with automated NOE assignment using the new software CANDID and the torsion angle dynamics algorithm DYANA","volume":"319","author":"Herrmann","year":"2002","journal-title":"J. Mol. Biol."},{"key":"2021112215411364600_B31","first-page":"355","article-title":"MLEV-17-based two-dimensional homonuclear magnetization transfer spectroscopy","volume":"65","author":"Bax","year":"1985","journal-title":"J. Magn. Reson."},{"key":"2021112215411364600_B32","first-page":"402","article-title":"Theory and applications of the transferred nuclear Overhauser effect to the study of the conformations of small ligands bound to proteins","volume":"48","author":"Clore","year":"1982","journal-title":"J. Magn. Reson."},{"key":"2021112215411364600_B33","first-page":"423","article-title":"Theory of the time-dependent transferred nuclear Overhauser effect: applications to structural analysis of ligand\u2013protein complexes in solution","volume":"53","author":"Clore","year":"1983","journal-title":"J. Magn. Reson."},{"key":"2021112215411364600_B34","first-page":"301","article-title":"Correlation of proton and nitrogen-15 chemical shifts by multiple quantum NMR","volume":"55","author":"Bax","year":"1983","journal-title":"J. Magn. Reson."},{"key":"2021112215411364600_B35","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1006\/jmra.1993.1098","article-title":"Gradient-tailored water suppression for 1H-15N HSQC experiments optimized to retain full sensitivity","volume":"102","author":"Sklenar","year":"1993","journal-title":"J. Magn. Reson."},{"key":"2021112215411364600_B36","doi-asserted-by":"crossref","first-page":"6108","DOI":"10.1021\/ja0100120","article-title":"Group epitope mapping by saturation transfer difference NMR to identify segments of a ligand in direct contact with a protein receptor","volume":"123","author":"Mayer","year":"2001","journal-title":"J. Am. Chem. Soc."},{"key":"2021112215411364600_B37","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1006\/jmbi.1993.1626","article-title":"Comparative protein modelling by satisfaction of spatial restraints","volume":"234","author":"Sali","year":"1993","journal-title":"J. Mol. Biol."},{"key":"2021112215411364600_B38","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1016\/S0076-6879(03)74020-8","article-title":"Modeller: generation and refinement of homology-based protein structure models","volume":"374","author":"Fiser","year":"2003","journal-title":"Methods Enzymol."},{"key":"2021112215411364600_B39","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1038\/nprot.2010.32","article-title":"The HADDOCK web server for data-driven biomolecular docking","volume":"5","author":"de Vries","year":"2010","journal-title":"Nat. Protoc."},{"key":"2021112215411364600_B40","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1038\/nrc2396","article-title":"Deregulated proteolysis by the F-box proteins SKP2 and \u03b2-TrCP: tipping the scales of cancer","volume":"8","author":"Frescas","year":"2008","journal-title":"Nat. Rev. Cancer"},{"key":"2021112215411364600_B41","doi-asserted-by":"crossref","first-page":"W473","DOI":"10.1093\/nar\/gkm423","article-title":"PIC: Protein Interactions Calculator","volume":"35","author":"Tina","year":"2007","journal-title":"Nucleic Acids Res."},{"key":"2021112215411364600_B42","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1038\/sj.onc.1202653","article-title":"The human F box protein \u03b2-Trcp associates with the Cul1\/Skp1 complex and regulates the stability of \u03b2-catenin","volume":"18","author":"Latres","year":"1999","journal-title":"Oncogene"},{"key":"2021112215411364600_B43","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1101\/gad.13.3.270","article-title":"The SCF\u03b2-TRCP\u2013ubiquitin ligase complex associates specifically with phosphorylated destruction motifs in I\u03baB\u03b1 and \u03b2-catenin and stimulates I\u03baB\u03b1 ubiquitination in\u00a0vitro","volume":"13","author":"Winston","year":"1999","journal-title":"Genes Dev."},{"key":"2021112215411364600_B44","doi-asserted-by":"crossref","first-page":"9858","DOI":"10.1073\/pnas.152294299","article-title":"Ligand-independent growth hormone receptor dimerization occurs in the endoplasmic reticulum and is required for ubiquitin system-dependent endocytosis","volume":"99","author":"Gent","year":"2002","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2021112215411364600_B45","doi-asserted-by":"crossref","first-page":"15533","DOI":"10.1074\/jbc.M111.302521","article-title":"Ubc13 and COOH terminus of Hsp70-interacting protein (CHIP) are required for growth hormone receptor endocytosis","volume":"287","author":"Slotman","year":"2012","journal-title":"J. Biol. Chem."},{"key":"2021112215411364600_B46","doi-asserted-by":"crossref","first-page":"9459","DOI":"10.1073\/pnas.96.17.9459","article-title":"Cation\u2013\u03c0 interactions in structural biology","volume":"96","author":"Gallivan","year":"1999","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2021112215411364600_B47","doi-asserted-by":"crossref","first-page":"1359","DOI":"10.1021\/cr960370z","article-title":"Molecular recognition of protein\u2013ligand complexes: applications to drug design","volume":"97","author":"Babine","year":"1997","journal-title":"Chem. Rev."},{"key":"2021112215411364600_B48","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/j.jmgm.2005.12.002","article-title":"Molecular modeling, docking and ADMET studies applied to the design of a novel hybrid for treatment of Alzheimer's disease","volume":"25","author":"da Silva","year":"2006","journal-title":"J. Mol. Graphics Model."},{"key":"2021112215411364600_B49","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1038\/ncomms1351","article-title":"Molecular basis for class Ib anti-arrhythmic inhibition of cardiac sodium channels","volume":"2","author":"Pless","year":"2011","journal-title":"Nat. Commun."}],"container-title":["Biochemical Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/portlandpress.com\/biochemj\/article-pdf\/453\/2\/291\/674145\/bj4530291.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/portlandpress.com\/biochemj\/article-pdf\/453\/2\/291\/674145\/bj4530291.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,11,22]],"date-time":"2021-11-22T21:50:45Z","timestamp":1637617845000},"score":1,"resource":{"primary":{"URL":"https:\/\/portlandpress.com\/biochemj\/article\/453\/2\/291\/46250\/TrCP-interacts-with-the-ubiquitin-dependent"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,6,28]]},"references-count":49,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2013,7,15]]}},"URL":"https:\/\/doi.org\/10.1042\/bj20121843","relation":{},"ISSN":["0264-6021","1470-8728"],"issn-type":[{"value":"0264-6021","type":"print"},{"value":"1470-8728","type":"electronic"}],"subject":[],"published":{"date-parts":[[2013,6,28]]}}}