{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T12:13:43Z","timestamp":1767960823097,"version":"3.49.0"},"reference-count":36,"publisher":"Oxford University Press (OUP)","issue":"7","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2006,4,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Summary: Down syndrome (DS) is the most frequent form of mental retardation and is caused by chromosome 21 (HSA21) trisomy. Despite the number of known genes involved in DS and its high therapeutic interest, biological mechanisms leading to the DS phenotype are not fully clear. We present a functional hypothesis based on fold recognition and hidden Markov model techniques for four HSA21 genes located in the DS Candidate Region (DSCR). More specifically, we propose that they are members of a novel mitogen-activated protein kinase pathway with DYRK1A, SNF1LK and RIPK4 gene products being elements of the kinase cascade and the DSCR3 acting as structural scaffold for their interaction. This hypothesis finds support in various biochemical studies concerning the biological behavior and features of the involved HSA21 proteins. Our analysis calls for specifically designed experiments to validate our prediction and establish its relevance in terms of therapeutic approaches to the disease.<\/jats:p>\n               <jats:p>Contact: \u00a0anna.tramontano@uniroma1.it<\/jats:p>\n               <jats:p>Suplementary information: Supplementary data are available at Bioinformatics online.<\/jats:p>","DOI":"10.1093\/bioinformatics\/btl006","type":"journal-article","created":{"date-parts":[[2006,1,21]],"date-time":"2006-01-21T01:32:41Z","timestamp":1137807161000},"page":"775-778","source":"Crossref","is-referenced-by-count":10,"title":["Identification of a novel putative mitogen-activated kinase cascade on human chromosome 21 by computational approaches"],"prefix":"10.1093","volume":"22","author":[{"given":"Marialuisa","family":"Pellegrini-Calace","sequence":"first","affiliation":[{"name":"Department of Biochemical Sciences \u2018Rossi-Fanelli\u2019, University \u2018La Sapienza\u2019 1 \u00a0 1 \u00a0 \u00a0 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Tramontano","sequence":"additional","affiliation":[{"name":"Department of Biochemical Sciences \u2018Rossi-Fanelli\u2019, University \u2018La Sapienza\u2019 1 \u00a0 1 \u00a0 \u00a0 Rome, Italy"},{"name":"Istituto Pasteur Fondazione \u2018Cenci-Bolognetti\u2019 2 \u00a0 2 \u00a0 \u00a0 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2006,1,20]]},"reference":[{"key":"2023012409115989500_b1","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1016\/S0022-2836(05)80360-2","article-title":"Basic local alignment search tool","volume":"215","author":"Altschul","year":"1990","journal-title":"J. Mol. Biol."},{"key":"2023012409115989500_b2","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1038\/75556","article-title":"Gene ontology: tool for the unification of biology. The Gene Ontology Consortium","volume":"25","author":"Ashburner","year":"2000","journal-title":"Nat. Genet."},{"key":"2023012409115989500_b3","doi-asserted-by":"crossref","first-page":"3915","DOI":"10.1073\/pnas.0400272101","article-title":"Acute myeloid leukemia with complex karyotypes and abnormal chromosome 21: Amplification discloses overexpression of APP, ETS2, and ERG genes","volume":"101","author":"Baldus","year":"2004","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2023012409115989500_b4","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1093\/nar\/30.1.276","article-title":"The Pfam protein families database","volume":"30","author":"Bateman","year":"2002","journal-title":"Nucleic Acids Res."},{"key":"2023012409115989500_b5","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1093\/nar\/28.1.235","article-title":"The Protein Data Bank","volume":"28","author":"Berman","year":"2000","journal-title":"Nucleic Acids Res."},{"key":"2023012409115989500_b6","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/j.tig.2005.02.010","article-title":"Dosage balance in gene regulation: biological implications","volume":"21","author":"Birchler","year":"2005","journal-title":"Trends Genet."},{"key":"2023012409115989500_b7","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1093\/jnen\/63.5.429","article-title":"Transgenic mouse in vivo library of human Down syndrome critical region 1: association between DYRK1A overexpression, brain development abnormalities, and cell cycle protein alteration","volume":"63","author":"Branchi","year":"2004","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"2023012409115989500_b8","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1159\/000472398","article-title":"Molecular mapping of twenty-four features of Down syndrome on chromosome 21","volume":"1","author":"Delabar","year":"1993","journal-title":"Eur. J. Hum. Genet."},{"key":"2023012409115989500_b9","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1093\/bioinformatics\/14.9.755","article-title":"Profile hidden Markov models","volume":"14","author":"Eddy","year":"1998","journal-title":"Bioinformatics"},{"key":"2023012409115989500_b10","first-page":"207","article-title":"Protocols to establish genotype\u2013phenotype correlations in Down syndrome","volume":"49","author":"Epstein","year":"1991","journal-title":"Am. J. Hum. Genet."},{"key":"2023012409115989500_b11","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1007\/978-3-7091-6721-2_12","article-title":"The MNB\/DYRK1A protein kinase: genetic and biochemical properties","volume":"67","author":"Galceran","year":"2003","journal-title":"J Neural Transm Suppl."},{"key":"2023012409115989500_b12","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/S0378-1119(03)00769-8","article-title":"Mouse models of Down syndrome: how useful can they be? Comparison of the gene content of human chromosome 21 with orthologous mouse genomic regions.","volume":"318","author":"Gardiner","year":"2003","journal-title":"Gene"},{"key":"2023012409115989500_b13","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1159\/000081518","article-title":"Report on the \u2018Expert Workshop on the Biology of Chromosome 21: towards gene-phenotype correlations in Down syndrome\u2019, held June 11\u201314, 2004, Washington D.C","volume":"108","author":"Gardiner","year":"2005","journal-title":"Cytogenet. Genome Res."},{"key":"2023012409115989500_b14","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1182\/blood-2003-05-1556","article-title":"Recent insights into the mechanisms of myeloid leukemogenesis in Down syndrome","volume":"103","author":"Gurbuxani","year":"2004","journal-title":"Blood"},{"key":"2023012409115989500_b15","doi-asserted-by":"crossref","first-page":"4105","DOI":"10.1091\/mbc.11.12.4105","article-title":"Human orthologs of yeast vacuolar protein sorting proteins Vps26, 29, and 35: assembly into multimeric complexes","volume":"11","author":"Haft","year":"2000","journal-title":"Mol. Biol. Cell"},{"key":"2023012409115989500_b16","doi-asserted-by":"crossref","first-page":"2277","DOI":"10.1046\/j.1460-9568.2003.02665.x","article-title":"Expression patterns and subcellular localization of the Down syndrome candidate protein MNB\/DYRK1A suggest a role in late neuronal differentiation","volume":"17","author":"Hammerle","year":"2003","journal-title":"Eur. J. Neurosci."},{"key":"2023012409115989500_b17","doi-asserted-by":"crossref","first-page":"D514","DOI":"10.1093\/nar\/gki033","article-title":"Online Mendelian Inheritance in Man (OMIM), a knowledgebase of human genes and genetic disorders","volume":"33","author":"Hamosh","year":"2005","journal-title":"Nucleic Acids Res."},{"key":"2023012409115989500_b18","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1046\/j.1365-2443.2003.00650.x","article-title":"AKRL1 and AKRL2 activate the JNK pathway","volume":"8","author":"Harada","year":"2003","journal-title":"Genes Cells"},{"key":"2023012409115989500_b19","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1038\/35012518","article-title":"The DNA sequence of human chromosome 21 [Erratum (2000) Nature, 407, 110.]","volume":"18","author":"Hattori","year":"2000","journal-title":"Nature"},{"key":"2023012409115989500_b20","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/S0092-8674(00)80735-7","article-title":"The 2.8 \u00c5 crystal structure of visual arrestin: a model for arrestin's regulation","volume":"97","author":"Hirsch","year":"1999","journal-title":"Cell"},{"key":"2023012409115989500_b21","doi-asserted-by":"crossref","first-page":"D447","DOI":"10.1093\/nar\/gki138","article-title":"Ensembl 2005","volume":"33","author":"Hubbard","year":"2005","journal-title":"Nucleic Acids Res."},{"key":"2023012409115989500_b22","doi-asserted-by":"crossref","first-page":"3562","DOI":"10.1091\/mbc.e04-12-1085","article-title":"DYRK1A enhances the mitogen-activated protein kinase cascade in PC12 cells by forming a complex with Ras, B-Raf, and MEK1","volume":"16","author":"Kelly","year":"2005","journal-title":"Mol. Biol. Cell"},{"key":"2023012409115989500_b23","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1016\/j.ceb.2004.01.001","article-title":"beta-arrestins: traffic cops of cell signalling","volume":"16","author":"Lefkowitz","year":"2004","journal-title":"Curr. Opin. Cell Biol."},{"key":"2023012409115989500_b24","doi-asserted-by":"crossref","first-page":"14706","DOI":"10.1074\/jbc.274.21.14706","article-title":"The ankyrin repeat-containing adaptor protein Tvl-1 is a novel substrate and regulator of Raf-1","volume":"274","author":"Lin","year":"1999","journal-title":"J. Biol. Chem."},{"key":"2023012409115989500_b25","doi-asserted-by":"crossref","first-page":"1912","DOI":"10.1126\/science.1075762","article-title":"The protein kinase complement of the human genome","volume":"298","author":"Manning","year":"2002","journal-title":"Science"},{"key":"2023012409115989500_b26","doi-asserted-by":"crossref","first-page":"874","DOI":"10.1093\/bioinformatics\/btg097","article-title":"Improvement of the GenTHREADER method for genomic fold recognition","volume":"19","author":"McGuffin","year":"2003","journal-title":"Bioinformatics"},{"key":"2023012409115989500_b27","doi-asserted-by":"crossref","first-page":"1202","DOI":"10.1093\/embo-reports\/kvf236","article-title":"RIP4 (DIK\/PIKK), a novel member of the RIP kinase family, activates NF-kB and is processed during apoptosis","volume":"3","author":"Meylan","year":"2002","journal-title":"EMBO reports"},{"key":"2023012409115989500_b28","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/j.tibs.2005.01.003","article-title":"The RIP kinases: crucial integrators of cellular stress","volume":"30","author":"Meylan","year":"2005","journal-title":"Trends Biochem. Sci."},{"key":"2023012409115989500_b29","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1006\/bbrc.1999.1705","article-title":"Distantly related cousins of MAP kinase: biochemical properties and possible physiological functions","volume":"266","author":"Miyata","year":"1999","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"2023012409115989500_b30","doi-asserted-by":"crossref","first-page":"1435","DOI":"10.1110\/ps.03554604","article-title":"The ankyrin repeat as molecular architecture for protein recognition","volume":"13","author":"Mosavi","year":"2004","journal-title":"Protein Sci."},{"key":"2023012409115989500_b31","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.gene.2005.07.019","article-title":"Human chromosome 21\/Down syndrome gene function and pathway database","volume":"364","author":"Nikolaienko","year":"2005","journal-title":"Gene"},{"key":"2023012409115989500_b32","doi-asserted-by":"crossref","first-page":"D501","DOI":"10.1093\/nar\/gki025","article-title":"NCBI Reference Sequence (RefSeq): a curated non-redundant sequence database of genomes, transcripts and proteins","volume":"33","author":"Pruitt","year":"2005","journal-title":"Nucleic Acids Res."},{"key":"2023012409115989500_b33","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1110\/ps.04888805","article-title":"LiveBench-8: the large-scale, continuous assessment of automated protein structure prediction","volume":"14","author":"Rychlewski","year":"2005","journal-title":"Protein Sci."},{"key":"2023012409115989500_b34","doi-asserted-by":"crossref","first-page":"2711","DOI":"10.1111\/j.0953-816X.2004.03365.x","article-title":"Increased MAP kinase activity in Alzheimer's and Down syndrome but not in schizophrenia human brain","volume":"19","author":"Swatton","year":"2004","journal-title":"Eur. J. Neurosci."},{"key":"2023012409115989500_b35","doi-asserted-by":"crossref","first-page":"4673","DOI":"10.1093\/nar\/22.22.4673","article-title":"CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice","volume":"22","author":"Thompson","year":"1994","journal-title":"Nucleic Acids Res."},{"key":"2023012409115989500_b36","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1016\/S0968-0004(98)01309-7","article-title":"Structural organization of MAP-kinase signalling modules by scaffold proteins in yeast and mammals","volume":"23","author":"Whitmarsh","year":"1998","journal-title":"Trends Biochem. Sci."}],"container-title":["Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/22\/7\/775\/48840627\/bioinformatics_22_7_775.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/22\/7\/775\/48840627\/bioinformatics_22_7_775.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,24]],"date-time":"2023-01-24T09:48:05Z","timestamp":1674553685000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article\/22\/7\/775\/202390"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2006,1,20]]},"references-count":36,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2006,4,1]]}},"URL":"https:\/\/doi.org\/10.1093\/bioinformatics\/btl006","relation":{},"ISSN":["1367-4811","1367-4803"],"issn-type":[{"value":"1367-4811","type":"electronic"},{"value":"1367-4803","type":"print"}],"subject":[],"published-other":{"date-parts":[[2006,4,1]]},"published":{"date-parts":[[2006,1,20]]}}}