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PMID:21282464

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Citation

Coene, ED, Gadelha, C, White, N, Malhas, A, Thomas, B, Shaw, M and Vaux, DJ (2011) A novel role for BRCA1 in regulating breast cancer cell spreading and motility. J. Cell Biol. 192:497-512

Abstract

BRCA1 C-terminal (BRCT) domains in BRCA1 are essential for tumor suppressor function, though the underlying mechanisms remain unclear. We identified ezrin, radixin, and moesin as BRCA1 BRCT domain-interacting proteins. Ezrin-radixin-moesin (ERM) and F-actin colocalized with BRCA1 at the plasma membrane (PM) of cancer cells, especially at leading edges and focal adhesion sites. In stably expressing cancer cells, high levels of enhanced green fluorescent protein (EGFP)-BRCA1(1634-1863) acted as a dominant-negative factor, displacing endogenous BRCA1 from the PM. This led to delayed cell spreading, increased spontaneous motility, and irregular monolayer wound healing. MCF-7 cells (intact BRCA1) showed lower motility than HCC1937 cells (truncated BRCA1), but expression of EGFP-BRCA1(1634-1863) in MCF-7 increased motility. Conversely, full-length BRCA1 expression in HCC1937 decreased motility but only if the protein retained ubiquitin ligase activity. We conclude that full-length BRCA1 is important for complete tumor suppressor activity via interaction of its BRCT domains with ERM at the PM, controlling spreading and motility of cancer cells via ubiquitin ligase activity.

Links

PubMed PMC3101087 Online version:10.1083/jcb.201004136

Keywords

Animals; BRCA1 Protein/genetics; BRCA1 Protein/metabolism; BRCA1 Protein/physiology; Breast Neoplasms/enzymology; Breast Neoplasms/genetics; Breast Neoplasms/metabolism; CHO Cells; Cell Line, Tumor; Cell Movement/genetics; Cricetinae; Cricetulus; Female; HeLa Cells; Humans; Transfection; Ubiquitin-Protein Ligases/genetics; Ubiquitin-Protein Ligases/metabolism; Ubiquitin-Protein Ligases/physiology

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:MOES

colocalizes_with

GO:0005925: focal adhesion

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:RADI

colocalizes_with

GO:0005925: focal adhesion

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:BRCA1

located_in

GO:0005886: plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:F5H1A7

colocalizes_with

GO:0005925: focal adhesion

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:EZRI

colocalizes_with

GO:0005925: focal adhesion

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:BRCA1

part_of

GO:0005886: plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete


See also

References

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