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.
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16 August 2004
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August 16 2004
Raf-1 activation disrupts its binding to keratins during cell stress
Nam-On Ku,
Nam-On Ku
1Department of Medicine, VA Palo Alto Medical Center and Stanford University Digestive Disease Center, Palo Alto, CA 94304
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Haian Fu,
Haian Fu
2Department of Pharmacology, Emory University, Atlanta, GA 30322
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M. Bishr Omary
M. Bishr Omary
1Department of Medicine, VA Palo Alto Medical Center and Stanford University Digestive Disease Center, Palo Alto, CA 94304
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Nam-On Ku
1Department of Medicine, VA Palo Alto Medical Center and Stanford University Digestive Disease Center, Palo Alto, CA 94304
Haian Fu
2Department of Pharmacology, Emory University, Atlanta, GA 30322
M. Bishr Omary
1Department of Medicine, VA Palo Alto Medical Center and Stanford University Digestive Disease Center, Palo Alto, CA 94304
Address correspondence to Nam-On Ku, VA Palo Alto Medical Center, 3801 Miranda Ave., 154J, Palo Alto, CA 94304. Fax: (650) 852-3259
Abbreviations used in this paper: Ab, antibody; Emp, Empigen; MLR, microcystin-LR; OA, okadaic acid; WT, wild-type.
Received:
February 09 2004
Accepted:
June 23 2004
Online ISSN: 1540-8140
Print ISSN: 0021-9525
The Rockefeller University Press
2004
J Cell Biol (2004) 166 (4): 479–485.
Article history
Received:
February 09 2004
Accepted:
June 23 2004
Citation
Nam-On Ku, Haian Fu, M. Bishr Omary; Raf-1 activation disrupts its binding to keratins during cell stress . J Cell Biol 16 August 2004; 166 (4): 479–485. doi: https://doi.org/10.1083/jcb.200402051
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