CIB1 functions as a Ca(2+)-sensitive modulator of stress-induced signaling by targeting ASK1

Proc Natl Acad Sci U S A. 2009 Oct 13;106(41):17389-94. doi: 10.1073/pnas.0812259106. Epub 2009 Sep 29.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Annexin A5 / pharmacology
  • Basic Helix-Loop-Helix Transcription Factors / chemistry
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Calcium / metabolism
  • Calcium-Binding Proteins / chemistry
  • Calcium-Binding Proteins / genetics
  • Calcium-Binding Proteins / metabolism*
  • Flow Cytometry
  • Fluorescein-5-isothiocyanate
  • Genetic Variation
  • MAP Kinase Kinase Kinase 5 / genetics
  • MAP Kinase Kinase Kinase 5 / metabolism*
  • Mesencephalon / embryology
  • Mesencephalon / physiology
  • Neurons / physiology
  • Oxidation-Reduction
  • Oxidopamine / pharmacology
  • Propidium / pharmacology
  • RNA Interference
  • Signal Transduction
  • TNF Receptor-Associated Factor 2 / chemistry
  • TNF Receptor-Associated Factor 2 / metabolism
  • TNF Receptor-Associated Factor 6 / chemistry
  • TNF Receptor-Associated Factor 6 / metabolism
  • Tumor Necrosis Factor-alpha / pharmacology

Substances

  • Annexin A5
  • Basic Helix-Loop-Helix Transcription Factors
  • Calcium-Binding Proteins
  • Cib1 protein, rat
  • TNF Receptor-Associated Factor 2
  • TNF Receptor-Associated Factor 6
  • Tumor Necrosis Factor-alpha
  • Propidium
  • Oxidopamine
  • MAP Kinase Kinase Kinase 5
  • Fluorescein-5-isothiocyanate
  • Calcium