CIB1 functions as a Ca(2+)-sensitive modulator of stress-induced signaling by targeting ASK1.
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.
Yoon
Kyoung Wan
KW
Laboratories of Cell Death and Human Diseases, School of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Korea.
Cho
Jun-Ho
JH
Lee
Jae Keun
JK
Kang
Young-Hee
YH
Chae
Ji Soo
JS
Kim
Young Mok
YM
Kim
Jeehyun
J
Kim
Eun Kyung
EK
Kim
Sung Eun
SE
Baik
Ja-Hyun
JH
Naik
Ulhas P
UP
Cho
Ssang-Goo
SG
Choi
Eui-Ju
EJ
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
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