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Published 16 August 2004. doi:10.1083/jcb.200402051
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 166, Number 4, 479-485
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Report

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

Nam-On Ku1, Haian Fu2, and M. Bishr Omary1

1 Department of Medicine, VA Palo Alto Medical Center and Stanford University Digestive Disease Center, Palo Alto, CA 94304
2 Department of Pharmacology, Emory University, Atlanta, GA 30322

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


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.

Key Words: keratins; Raf-1 kinase; intermediate filaments; 14-3-3 proteins; cell stress

Abbreviations used in this paper: Ab, antibody; Emp, Empigen; MLR, microcystin-LR; OA, okadaic acid; WT, wild-type.


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