Fbw7 (F-box WD40 protein 7) is a major tumour suppressor, which mediates the degradation of several potent oncogenes. PKC (protein kinase C) comprises a serine/threonine kinase family that can promote transformation when dysregulated. In the present study, we investigated the relationship between Fbw7 and PKC. Multiple members of the PKC superfamily interact with the substrate-binding domain of Fbw7. However, we find no evidence for Fbw7-mediated degradation of PKC. Instead, we demonstrate that Fbw7 is a novel substrate for PKC. Two residues within the isoform-specific N-terminus of Fbw7α are phosphorylated in a PKC-dependent manner, both in vitro and in mammalian cells (Ser10 and Ser18). Mutational analyses reveal that phosphorylation of Fbw7α at Ser10 can regulate its nuclear localization. Cancer-associated mutations in nearby residues (K11R and the addition of a proline residue at position 16) influence Fbw7α localization in a comparable manner, suggesting that mislocalization of this protein may be of pathological significance. Together these results provide evidence for both physical and functional interactions between the PKC and Fbw7 families, and yield insights into the isoform-specific regulation of Fbw7α.
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Research Article|
October 25 2010
Regulation of the tumour suppressor Fbw7α by PKC-dependent phosphorylation and cancer-associated mutations
Joanne Durgan;
Joanne Durgan
*Protein Phosphorylation Laboratory, London Research Institute, Cancer Research UK, 44 Lincoln Inn's Fields, London WC2A 3PX, U.K.
†Cell Biology Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, U.S.A.
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Peter J. Parker
Peter J. Parker
1
*Protein Phosphorylation Laboratory, London Research Institute, Cancer Research UK, 44 Lincoln Inn's Fields, London WC2A 3PX, U.K.
‡Division of Cancer Studies, King's College London, Guy's Campus, London SE11 1UL, U.K.
1To whom correspondence should be addressed (email peter.parker@cancer.org.uk).
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Publisher: Portland Press Ltd
Received:
June 02 2010
Revision Received:
August 05 2010
Accepted:
September 03 2010
Accepted Manuscript online:
September 03 2010
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2010 Biochemical Society
2010
Biochem J (2010) 432 (1): 77–87.
Article history
Received:
June 02 2010
Revision Received:
August 05 2010
Accepted:
September 03 2010
Accepted Manuscript online:
September 03 2010
Citation
Joanne Durgan, Peter J. Parker; Regulation of the tumour suppressor Fbw7α by PKC-dependent phosphorylation and cancer-associated mutations. Biochem J 15 November 2010; 432 (1): 77–87. doi: https://doi.org/10.1042/BJ20100799
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