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.
| Original language | English |
|---|---|
| Pages (from-to) | 479-485 |
| Number of pages | 7 |
| Journal | Journal of Cell Biology |
| Volume | 166 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - 2004 Aug 16 |
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All Science Journal Classification (ASJC) codes
- Cell Biology
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Raf-1 activation disrupts its binding to keratins during cell stress. / Ku, Nam On; Fu, Haian; Omary, M. Bishr.
In: Journal of Cell Biology, Vol. 166, No. 4, 16.08.2004, p. 479-485.Research output: Contribution to journal › Article
TY - JOUR
T1 - Raf-1 activation disrupts its binding to keratins during cell stress
AU - Ku, Nam On
AU - Fu, Haian
AU - Omary, M. Bishr
PY - 2004/8/16
Y1 - 2004/8/16
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=4143116817&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=4143116817&partnerID=8YFLogxK
U2 - 10.1083/jcb.200402051
DO - 10.1083/jcb.200402051
M3 - Article
C2 - 15314064
AN - SCOPUS:4143116817
VL - 166
SP - 479
EP - 485
JO - Journal of Cell Biology
JF - Journal of Cell Biology
SN - 0021-9525
IS - 4
ER -