CIB1 functions as a Ca2+-sensitive modulator of stress-induced signaling by targeting ASK1

Wan Yoon Kyoung, Jun Ho Cho, Keun Lee Jae, Young Hee Kang, Soo Chae Ji, Mok Kim Young, Jeehyun Kim, Kyung Kim Eun, Eun Kim Sung, Ja-Hyun Baik, Ulhas P. Naik, Ssang Goo Cho, Eui Ju Choi

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30 Citations (Scopus)

Abstract

Calcium and integrin binding protein 1 (CIB1) is a Ca2+-binding protein of 22 kDa that was initially identified as a protein that interacts with integrin αIIb. 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-α in breast cancer MCF7 cells or by 6-hydroxydopamine (6-OHDA) in dopaminergic cells. Ca2+ 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 Ca2+-sensitive negative regulator of ASK1-mediated signaling events.

Original languageEnglish
Pages (from-to)17389-17394
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number41
DOIs
Publication statusPublished - 2009 Oct 13

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Keywords

  • Apoptosis
  • Calcium
  • MAPK

ASJC Scopus subject areas

  • General

Cite this

Kyoung, W. Y., Cho, J. H., Jae, K. L., Kang, Y. H., Ji, S. C., Young, M. K., Kim, J., Eun, K. K., Sung, E. K., Baik, J-H., Naik, U. P., Cho, S. G., & Choi, E. J. (2009). CIB1 functions as a Ca2+-sensitive modulator of stress-induced signaling by targeting ASK1. Proceedings of the National Academy of Sciences of the United States of America, 106(41), 17389-17394. https://doi.org/10.1073/pnas.0812259106