title: CIB1 functions as a Ca(2+)-sensitive modulator of stress-induced signaling by targeting ASK1.
abstract: Calcium and integrin binding protein 1 (CIB1) is a Ca(2+)-binding protein of 22 kDa that was initially identified as a protein that interacts with integrin alpha(IIb). Although it interacts with various proteins and has been implicated in diverse cellular functions, the molecular mechanism by which CIB1 regulates intracellular signaling networks has remained unclear. We now show that, by targeting apoptosis signal-regulating kinase 1 (ASK1), CIB1 negatively regulates stress-activated MAPK signaling pathways. CIB1 was thus shown to bind to ASK1, to interfere with the recruitment of TRAF2 to ASK1, and to inhibit the autophosphorylation of ASK1 on threonine-838, thereby blocking ASK1 activation. Furthermore, CIB1 mitigated apoptotic cell death initiated either by TNF-alpha in breast cancer MCF7 cells or by 6-hydroxydopamine (6-OHDA) in dopaminergic cells. Ca(2+) influx induced by membrane depolarization reversed the inhibitory effect of CIB1 on 6-OHDA-induced ASK1 activation and cell death in dopaminergic neurons. These observations thus suggest that CIB1 functions as a Ca(2+)-sensitive negative regulator of ASK1-mediated signaling events.
authors.affiliation: Laboratories of Cell Death and Human Diseases, School of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Korea.
authors.forename: Kyoung Wan
authors.initials: KW
authors.lastname: Yoon
authors.forename: Jun-Ho
authors.initials: JH
authors.lastname: Cho
authors.forename: Jae Keun
authors.initials: JK
authors.lastname: Lee
authors.forename: Young-Hee
authors.initials: YH
authors.lastname: Kang
authors.forename: Ji Soo
authors.initials: JS
authors.lastname: Chae
authors.forename: Young Mok
authors.initials: YM
authors.lastname: Kim
authors.forename: Jeehyun
authors.initials: J
authors.lastname: Kim
authors.forename: Eun Kyung
authors.initials: EK
authors.lastname: Kim
authors.forename: Sung Eun
authors.initials: SE
authors.lastname: Kim
authors.forename: Ja-Hyun
authors.initials: JH
authors.lastname: Baik
authors.forename: Ulhas P
authors.initials: UP
authors.lastname: Naik
authors.forename: Ssang-Goo
authors.initials: SG
authors.lastname: Cho
authors.forename: Eui-Ju
authors.initials: EJ
authors.lastname: Choi
mesh_terms: D017304:Annexin A5 / Q000494:pharmacology; D051792:Basic Helix-Loop-Helix Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D005434:Flow Cytometry; D016650:Fluorescein-5-isothiocyanate; D014644:Genetic Variation; D048848:MAP Kinase Kinase Kinase 5 / Q000235:genetics / Q000378:metabolism*; D008636:Mesencephalon / Q000196:embryology / Q000502:physiology; D009474:Neurons / Q000502:physiology; D010084:Oxidation-Reduction; D016627:Oxidopamine / Q000494:pharmacology; D011419:Propidium / Q000494:pharmacology; D034622:RNA Interference; D015398:Signal Transduction; D047992:TNF Receptor-Associated Factor 2 / Q000737:chemistry / Q000378:metabolism; D048029:TNF Receptor-Associated Factor 6 / Q000737:chemistry / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D017304:Annexin A5; D051792:Basic Helix-Loop-Helix Proteins; D002118:Calcium; D002135:Calcium-Binding Proteins; D016650:Fluorescein-5-isothiocyanate; D048848:MAP Kinase Kinase Kinase 5; D016627:Oxidopamine; D011419:Propidium; D047992:TNF Receptor-Associated Factor 2; D048029:TNF Receptor-Associated Factor 6; D014409:Tumor Necrosis Factor-alpha; C491604:Cib1 protein, rat