{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T02:19:53Z","timestamp":1777429193388,"version":"3.51.4"},"reference-count":54,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,9,22]],"date-time":"2017-09-22T00:00:00Z","timestamp":1506038400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,9,22]],"date-time":"2017-09-22T00:00:00Z","timestamp":1506038400000},"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":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Calcium and integrin binding protein 1 (CIB1) is a calcium-binding protein that was initially identified as a binding partner of platelet integrin \u03b1<jats:sub>IIb<\/jats:sub>. Although CIB1 has been shown to interact with multiple proteins, its biological function in the brain remains unclear. Here, we show that CIB1 negatively regulates degeneration of dopaminergic neurons in a mouse model of Parkinson\u2019s disease using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Genetic deficiency of the CIB1 gene enhances MPTP-induced neurotoxicity in dopaminergic neurons in CIB1<jats:sup>\u2212\/\u2212<\/jats:sup> mice. Furthermore, RNAi-mediated depletion of CIB1 in primary dopaminergic neurons potentiated 1-methyl-4-phenyl pyrinidium (MPP<jats:sup>+<\/jats:sup>)-induced neuronal death. CIB1 physically associated with apoptosis signal-regulating kinase 1 (ASK1) and thereby inhibited the MPP<jats:sup>+<\/jats:sup>-induced stimulation of the ASK1-mediated signaling cascade. These findings suggest that CIB1 plays a protective role in MPTP\/MPP<jats:sup>+<\/jats:sup>-induced neurotoxicity by blocking ASK1-mediated signaling.<\/jats:p>","DOI":"10.1038\/s41598-017-12379-3","type":"journal-article","created":{"date-parts":[[2017,9,18]],"date-time":"2017-09-18T11:13:26Z","timestamp":1505733206000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["CIB1 protects against MPTP-induced neurotoxicity through inhibiting ASK1"],"prefix":"10.1038","volume":"7","author":[{"given":"Kyoung Wan","family":"Yoon","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hyun-Suk","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Young Mok","family":"Kim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yeonsil","family":"Kim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seongman","family":"Kang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1792-4894","authenticated-orcid":false,"given":"Woong","family":"Sun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ulhas P.","family":"Naik","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leslie V.","family":"Parise","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eui-Ju","family":"Choi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2017,9,22]]},"reference":[{"key":"12379_CR1","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1146\/annurev.neuro.28.061604.135718","volume":"28","author":"DJ Moore","year":"2005","unstructured":"Moore, D. J., West, A. B., Dawson, V. L. & Dawson, T. M. Molecular pathophysiology of Parkinson\u2019s disease. Annu Rev Neurosci \n                           28, 57\u201387, https:\/\/doi.org\/10.1146\/annurev.neuro.28.061604.135718 (2005).","journal-title":"Annu Rev Neurosci"},{"key":"12379_CR2","doi-asserted-by":"publisher","first-page":"1045","DOI":"10.2169\/internalmedicine.34.1045","volume":"34","author":"Y Mizuno","year":"1995","unstructured":"Mizuno, Y., Mori, H. & Kondo, T. Parkinson\u2019s disease: from etiology to treatment. Intern Med \n                           34, 1045\u20131054 (1995).","journal-title":"Intern Med"},{"key":"12379_CR3","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1146\/annurev.neuro.22.1.123","volume":"22","author":"CW Olanow","year":"1999","unstructured":"Olanow, C. W. & Tatton, W. G. Etiology and pathogenesis of Parkinson\u2019s disease. Annu Rev Neurosci \n                           22, 123\u2013144, https:\/\/doi.org\/10.1146\/annurev.neuro.22.1.123 (1999).","journal-title":"Annu Rev Neurosci"},{"issue":"Suppl 17","key":"12379_CR4","doi-asserted-by":"publisher","first-page":"S335","DOI":"10.1002\/mds.21675","volume":"22","author":"CW Olanow","year":"2007","unstructured":"Olanow, C. W. The pathogenesis of cell death in Parkinson\u2019s disease\u20132007. Mov Disord \n                           22(Suppl 17), S335\u2013342, https:\/\/doi.org\/10.1002\/mds.21675 (2007).","journal-title":"Mov Disord"},{"key":"12379_CR5","doi-asserted-by":"publisher","first-page":"1107","DOI":"10.2741\/2130","volume":"12","author":"C Mancuso","year":"2007","unstructured":"Mancuso, C. et al. Mitochondrial dysfunction, free radical generation and cellular stress response in neurodegenerative disorders. Front Biosci \n                           12, 1107\u20131123 (2007).","journal-title":"Front Biosci"},{"key":"12379_CR6","doi-asserted-by":"publisher","first-page":"1200","DOI":"10.1046\/j.1471-4159.2000.0751200.x","volume":"75","author":"MS Saporito","year":"2000","unstructured":"Saporito, M. S., Thomas, B. A. & Scott, R. W. MPTP activates c-Jun NH(2)-terminal kinase (JNK) and its upstream regulatory kinase MKK4 in nigrostriatal neurons in vivo. J Neurochem \n                           75, 1200\u20131208 (2000).","journal-title":"J Neurochem"},{"key":"12379_CR7","doi-asserted-by":"publisher","first-page":"10433","DOI":"10.1073\/pnas.181182298","volume":"98","author":"XG Xia","year":"2001","unstructured":"Xia, X. G. et al. Gene transfer of the JNK interacting protein-1 protects dopaminergic neurons in the MPTP model of Parkinson\u2019s disease. Proc Natl Acad Sci USA \n                           98, 10433\u201310438, https:\/\/doi.org\/10.1073\/pnas.181182298 (2001).","journal-title":"Proc Natl Acad Sci USA"},{"key":"12379_CR8","doi-asserted-by":"publisher","first-page":"1875","DOI":"10.2174\/138161207780858384","volume":"13","author":"T Borsello","year":"2007","unstructured":"Borsello, T. & Forloni, G. JNK signalling: a possible target to prevent neurodegeneration. Curr Pharm Des \n                           13, 1875\u20131886 (2007).","journal-title":"Curr Pharm Des"},{"key":"12379_CR9","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1016\/j.neures.2003.10.012","volume":"48","author":"W Wang","year":"2004","unstructured":"Wang, W. et al. SP600125, a new JNK inhibitor, protects dopaminergic neurons in the MPTP model of Parkinson\u2019s disease. Neurosci Res \n                           48, 195\u2013202 (2004).","journal-title":"Neurosci Res"},{"key":"12379_CR10","doi-asserted-by":"publisher","first-page":"234","DOI":"10.1111\/j.1471-4159.2006.03730.x","volume":"97","author":"M Ouyang","year":"2006","unstructured":"Ouyang, M. & Shen, X. Critical role of ASK1 in the 6-hydroxydopamine-induced apoptosis in human neuroblastoma SH-SY5Y cells. J Neurochem \n                           97, 234\u2013244, https:\/\/doi.org\/10.1111\/j.1471-4159.2006.03730.x (2006).","journal-title":"J Neurochem"},{"key":"12379_CR11","doi-asserted-by":"publisher","first-page":"2226","DOI":"10.1096\/fj.06-7580com","volume":"21","author":"S Karunakaran","year":"2007","unstructured":"Karunakaran, S. et al. Activation of apoptosis signal regulating kinase 1 (ASK1) and translocation of death-associated protein, Daxx, in substantia nigra pars compacta in a mouse model of Parkinson\u2019s disease: protection by alpha-lipoic acid. FASEB J \n                           21, 2226\u20132236, https:\/\/doi.org\/10.1096\/fj.06-7580com (2007).","journal-title":"FASEB J"},{"key":"12379_CR12","doi-asserted-by":"publisher","first-page":"8407","DOI":"10.1074\/jbc.M411515200","volume":"280","author":"HR Gentry","year":"2005","unstructured":"Gentry, H. R. et al. Structural and biochemical characterization of CIB1 delineates a new family of EF-hand-containing proteins. J Biol Chem \n                           280, 8407\u20138415, https:\/\/doi.org\/10.1074\/jbc.M411515200 (2005).","journal-title":"J Biol Chem"},{"key":"12379_CR13","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1002\/(SICI)1099-1352(200003\/04)13:2<83::AID-JMR491>3.0.CO;2-A","volume":"13","author":"PM Hwang","year":"2000","unstructured":"Hwang, P. M. & Vogel, H. J. Structures of the platelet calcium- and integrin-binding protein and the alphaIIb-integrin cytoplasmic domain suggest a mechanism for calcium-regulated recognition; homology modelling and NMR studies. J Mol Recognit \n                           13, 83\u201392, https:\/\/doi.org\/10.1002\/(SICI)1099-1352(200003\/04)13:2<83::AID-JMR491>3.0.CO;2-A (2000).","journal-title":"J Mol Recognit"},{"key":"12379_CR14","doi-asserted-by":"publisher","first-page":"4651","DOI":"10.1074\/jbc.272.8.4651","volume":"272","author":"UP Naik","year":"1997","unstructured":"Naik, U. P., Patel, P. M. & Parise, L. V. Identification of a novel calcium-binding protein that interacts with the integrin alphaIIb cytoplasmic domain. J Biol Chem \n                           272, 4651\u20134654 (1997).","journal-title":"J Biol Chem"},{"key":"12379_CR15","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1083\/jcb.200505131","volume":"172","author":"W Yuan","year":"2006","unstructured":"Yuan, W. et al. CIB1 is an endogenous inhibitor of agonist-induced integrin alphaIIbbeta3 activation. J Cell Biol \n                           172, 169\u2013175, https:\/\/doi.org\/10.1083\/jcb.200505131 (2006).","journal-title":"J Cell Biol"},{"key":"12379_CR16","doi-asserted-by":"publisher","first-page":"1185","DOI":"10.1161\/CIRCRESAHA.107.157586","volume":"101","author":"MA Zayed","year":"2007","unstructured":"Zayed, M. A. et al. CIB1 regulates endothelial cells and ischemia-induced pathological and adaptive angiogenesis. Circ Res \n                           101, 1185\u20131193, https:\/\/doi.org\/10.1161\/CIRCRESAHA.107.157586 (2007).","journal-title":"Circ Res"},{"key":"12379_CR17","doi-asserted-by":"publisher","first-page":"872","DOI":"10.1038\/nm.2181","volume":"16","author":"J Heineke","year":"2010","unstructured":"Heineke, J. et al. CIB1 is a regulator of pathological cardiac hypertrophy. Nat Med \n                           16, 872\u2013879, https:\/\/doi.org\/10.1038\/nm.2181 (2010).","journal-title":"Nat Med"},{"key":"12379_CR18","doi-asserted-by":"publisher","first-page":"3629","DOI":"10.1182\/blood-2003-05-1703","volume":"102","author":"MU Naik","year":"2003","unstructured":"Naik, M. U. & Naik, U. P. Calcium-and integrin-binding protein regulates focal adhesion kinase activity during platelet spreading on immobilized fibrinogen. Blood \n                           102, 3629\u20133636, https:\/\/doi.org\/10.1182\/blood-2003-05-1703 (2003).","journal-title":"Blood"},{"key":"12379_CR19","doi-asserted-by":"publisher","first-page":"5528","DOI":"10.1093\/emboj\/18.20.5528","volume":"18","author":"G Kauselmann","year":"1999","unstructured":"Kauselmann, G. et al. The polo-like protein kinases Fnk and Snk associate with a Ca(2+)- and integrin-binding protein and are regulated dynamically with synaptic plasticity. EMBO J \n                           18, 5528\u20135539, https:\/\/doi.org\/10.1093\/emboj\/18.20.5528 (1999).","journal-title":"EMBO J"},{"key":"12379_CR20","doi-asserted-by":"publisher","first-page":"8321","DOI":"10.1074\/jbc.M105363200","volume":"277","author":"L Haataja","year":"2002","unstructured":"Haataja, L., Kaartinen, V., Groffen, J. & Heisterkamp, N. The small GTPase Rac3 interacts with the integrin-binding protein CIB and promotes integrin alpha(IIb)beta(3)-mediated adhesion and spreading. J Biol Chem \n                           277, 8321\u20138328, https:\/\/doi.org\/10.1074\/jbc.M105363200 (2002).","journal-title":"J Biol Chem"},{"key":"12379_CR21","doi-asserted-by":"publisher","first-page":"465","DOI":"10.1083\/jcb.200502090","volume":"170","author":"TM Leisner","year":"2005","unstructured":"Leisner, T. M., Liu, M., Jaffer, Z. M., Chernoff, J. & Parise, L. V. Essential role of CIB1 in regulating PAK1 activation and cell migration. J Cell Biol \n                           170, 465\u2013476, https:\/\/doi.org\/10.1083\/jcb.200502090 (2005).","journal-title":"J Cell Biol"},{"key":"12379_CR22","doi-asserted-by":"publisher","first-page":"17389","DOI":"10.1073\/pnas.0812259106","volume":"106","author":"KW Yoon","year":"2009","unstructured":"Yoon, K. W. et al. CIB1 functions as a Ca(2+)-sensitive modulator of stress-induced signaling by targeting ASK1. Proc Natl Acad Sci USA \n                           106, 17389\u201317394, https:\/\/doi.org\/10.1073\/pnas.0812259106 (2009).","journal-title":"Proc Natl Acad Sci USA"},{"key":"12379_CR23","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1016\/S0921-8777(97)00035-9","volume":"385","author":"X Wu","year":"1997","unstructured":"Wu, X. & Lieber, M. R. Interaction between DNA-dependent protein kinase and a novel protein, KIP. Mutat Res \n                           385, 13\u201320 (1997).","journal-title":"Mutat Res"},{"key":"12379_CR24","doi-asserted-by":"publisher","first-page":"1277","DOI":"10.1083\/jcb.145.6.1277","volume":"145","author":"SM Stabler","year":"1999","unstructured":"Stabler, S. M., Ostrowski, L. L., Janicki, S. M. & Monteiro, M. J. A myristoylated calcium-binding protein that preferentially interacts with the Alzheimer\u2019s disease presenilin 2 protein. J Cell Biol \n                           145, 1277\u20131292 (1999).","journal-title":"J Cell Biol"},{"key":"12379_CR25","doi-asserted-by":"publisher","first-page":"120","DOI":"10.1016\/j.biocel.2010.10.003","volume":"43","author":"MU Naik","year":"2011","unstructured":"Naik, M. U. & Naik, U. P. Calcium- and integrin-binding protein 1 regulates microtubule organization and centrosome segregation through polo like kinase 3 during cell cycle progression. Int J Biochem Cell Biol \n                           43, 120\u2013129, https:\/\/doi.org\/10.1016\/j.biocel.2010.10.003 (2011).","journal-title":"Int J Biochem Cell Biol"},{"key":"12379_CR26","doi-asserted-by":"publisher","first-page":"538","DOI":"10.1046\/j.0014-2956.2001.02681.x","volume":"269","author":"C Whitehouse","year":"2002","unstructured":"Whitehouse, C. et al. NBR1 interacts with fasciculation and elongation protein zeta-1 (FEZ1) and calcium and integrin binding protein (CIB) and shows developmentally restricted expression in the neural tube. Eur J Biochem \n                           269, 538\u2013545 (2002).","journal-title":"Eur J Biochem"},{"key":"12379_CR27","doi-asserted-by":"publisher","first-page":"456","DOI":"10.1002\/ana.410200404","volume":"20","author":"JR Hotson","year":"1986","unstructured":"Hotson, J. R., Langston, E. B. & Langston, J. W. Saccade responses to dopamine in human MPTP-induced parkinsonism. 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Neurobiol Dis \n                           7, 240\u2013250, https:\/\/doi.org\/10.1006\/nbdi.2000.0319 (2000).","journal-title":"Neurobiol Dis"},{"key":"12379_CR32","doi-asserted-by":"publisher","first-page":"312","DOI":"10.1016\/j.freeradbiomed.2015.06.041","volume":"87","author":"A Ray","year":"2015","unstructured":"Ray, A., Sehgal, N., Karunakaran, S., Rangarajan, G. & Ravindranath, V. MPTP activates ASK1-p38 MAPK signaling pathway through TNF-dependent Trx1 oxidation in parkinsonism mouse model. Free Radic Biol Med \n                           87, 312\u2013325, https:\/\/doi.org\/10.1016\/j.freeradbiomed.2015.06.041 (2015).","journal-title":"Free Radic Biol Med"},{"key":"12379_CR33","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0029935","volume":"7","author":"KW Lee","year":"2012","unstructured":"Lee, K. W. et al. Apoptosis signal-regulating kinase 1 mediates MPTP toxicity and regulates glial activation. PLoS One \n                           7, e29935, https:\/\/doi.org\/10.1371\/journal.pone.0029935 (2012).","journal-title":"PLoS One"},{"key":"12379_CR34","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1146\/annurev.pharmtox.48.113006.094606","volume":"48","author":"K Takeda","year":"2008","unstructured":"Takeda, K., Noguchi, T., Naguro, I. & Ichijo, H. Apoptosis signal-regulating kinase 1 in stress and immune response. Annu Rev Pharmacol Toxicol \n                           48, 199\u2013225, https:\/\/doi.org\/10.1146\/annurev.pharmtox.48.113006.094606 (2008).","journal-title":"Annu Rev Pharmacol Toxicol"},{"key":"12379_CR35","doi-asserted-by":"publisher","first-page":"8152","DOI":"10.1128\/MCB.00227-07","volume":"27","author":"G Fujino","year":"2007","unstructured":"Fujino, G. et al. Thioredoxin and TRAF family proteins regulate reactive oxygen species-dependent activation of ASK1 through reciprocal modulation of the N-terminal homophilic interaction of ASK1. 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