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Author Notes:

Address correspondence to Nam-On Ku, VA Palo Alto Medical Center, 3801 Miranda Ave., 154J, Palo Alto, CA 94304. Fax: (650) 852-3259.

We are very grateful to Kris Morrow for preparing the figures.

Subjects:

Research Funding:

This work was supported by National Institutes of Health (NIH) grants DK52951 and VA Merit (to M.B. Omary), and NIH GM53165 (to H. Fu). N.-O. Ku is supported, in part, by a Veterans Administration Research Enhancement Award Program and an NIH Digestive Disease Center grant DK56339 pilot award.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Cell Biology
  • CELL BIOLOGY
  • keratins
  • Raf-1 kinase
  • intermediate filaments
  • 14-3-3 proteins
  • cell stress
  • 14-3-3 PROTEINS
  • INTERMEDIATE-FILAMENTS
  • CRYSTAL-STRUCTURE
  • PHOSPHORYLATION
  • KINASE
  • APOPTOSIS
  • DISEASE
  • PROGRESSION
  • ASSOCIATE
  • COFACTOR

Raf-1 activation disrupts its binding to keratins during cell stress

Journal Title:

Journal of Cell Biology

Volume:

Volume 166, Number 4

Publisher:

, Pages 479-485

Type of Work:

Article | Final Publisher PDF

Abstract:

Keratins 8 and 18 (K8/18) heteropolymers may regulate cell signaling via the known K18 association with 14-3-3 proteins and 14-3-3 association with Raf-1 kinase. We characterized Raf-keratin-14-3-3 associations and show that Raf associates directly with K8, independent of Raf kinase activity or Ras-Raf interaction, and that K18 is a Raf physiologic substrate. Raf activation during oxidative and toxin exposure in cultured cells and animals disrupt keratin-Raf association in a phosphorylation-dependent manner. Mutational analysis showed that 14-3-3 residues that are essential for Raf binding also regulate 14-3-3-keratin association. Similarly, Raf phosphorylation sites that are important for binding to 14-3-3 are also essential for Raf binding to K8/18. Therefore, keratins may modulate some aspects of Raf signaling under basal conditions via sequestration by K8, akin to Raf-14-3-3 binding. Keratin-bound Raf kinase is released upon Raf hyperphosphorylation and activation during oxidative and other stresses.

Copyright information:

© 2004, The Rockefeller University Press

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