Regulation of the tumour suppressor Fbw7α by PKC-dependent phosphorylation and cancer-associated mutations Journal Article
| Authors: | Durgan, J.; Parker, P. J. |
| Article Title: | Regulation of the tumour suppressor Fbw7α by PKC-dependent phosphorylation and cancer-associated mutations |
| Abstract: | Fbw7 (F-box WD40 protein 7) is a major tumour suppressor, whichmediates 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 proteinmay 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. © The Authors Journal compilation © 2010 Biochemical Society. |
| Keywords: | protein phosphorylation; unclassified drug; gene mutation; human cell; mutation; nonhuman; protein localization; neoplasms; proteins; mammalia; animals; cell cycle proteins; serine; enzyme degradation; protein protein interaction; protein binding; rna interference; in vitro study; hela cell; hela cells; transfection; cercopithecus aethiops; cos cells; phosphorylation; blotting, western; amino acid sequence; molecular sequence data; sequence homology, amino acid; tumors; sequence alignment; nucleotide sequence; isoforms; glutathione transferase; cellular distribution; green fluorescent proteins; microscopy, fluorescence; protein kinase c; cell nucleus; amino acids; tumor suppressor protein; mammals; catalytic domain; ubiquitin-protein ligases; protein isoforms; f-box proteins; nuclear localization; proline; two-hybrid system techniques; degradation; cancer-associated mutation; f-box wd40 protein 7 (fbw7); isoform-specific regulation; protein kinase c (pkc); cancer-associated mutations; oncogenic viruses; f box wd40 protein 7 alpha; hek293 cells |
| Journal Title: | Biochemical Journal |
| Volume: | 432 |
| Issue: | 1 |
| ISSN: | 0264-6021 |
| Publisher: | Portland Press Ltd |
| Date Published: | 2010-11-15 |
| Start Page: | 77 |
| End Page: | 87 |
| Language: | English |
| DOI: | 10.1042/bj20100799 |
| PUBMED: | 20815813 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Export Date: 20 April 2011" - "CODEN: BIJOA" - "Source: Scopus" |
