Domain and functional analysis of a novel breast tumor suppressor protein, SCUBE2

Yuh Charn Lin, Chun Chuan Chen, Chien Jui Cheng, Ruey Bing Yang

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Signal peptide CUB (complement proteins C1r/C1s, Uegf, and Bmp 1)-EGF domain-containing protein 2 (SCUBE2) is a secreted, membrane-associated multidomain protein composed of five recognizable motifs: an NH 2-terminal signal peptide sequence, nine copies of epidermal growth factor (EGF)-like repeats, a spacer region, three cysteine-rich repeats, and one CUB domain at the COOH terminus. Our previous clinical study showed that SCUBE2 may act as a novel breast tumor suppressor gene and serve as a useful prognostic marker. However, the specific domain responsible for its tumor suppressor activity and the precise mechanisms of its anti-tumor effect remain unknown. Using a combination of biochemical, molecular, and cell biology techniques, we further dissected the molecular functions and signal pathways mediated by the NH 2-terminal EGF-like repeats or COOH-terminal CUB domain of SCUBE2. Independent overexpression of the NH2-terminal EGF-like repeats or COOH-terminal CUB domain resulted in suppression of MCF-7 breast cancer cell proliferation and reduced MCF-7 xenograft tumor growth in nude mice. Molecular and biochemical analyses revealed that the COOH-terminal CUB domain could directly bind to and antagonize bone morphogenetic protein activity in an autocrine manner, whereas the NH 2-terminal EGF-like repeats could mediate cell-cell homophilic adhesions in a calcium-dependent fashion, interact with E-cadherin (a master tumor suppressor), and decrease the β-catenin signaling pathway. Together, our data demonstrate that SCUBE2 has growth inhibitory effects through a coordinated regulation of two distinct mechanisms: antagonizing bone morphogenetic protein and suppressing the β-catenin pathway in breast cancer cells.

Original languageEnglish
Pages (from-to)27039-27047
Number of pages9
JournalJournal of Biological Chemistry
Volume286
Issue number30
DOIs
Publication statusPublished - Jul 29 2011

Fingerprint

Tumor Suppressor Proteins
Functional analysis
Epidermal Growth Factor
Tumors
Breast Neoplasms
Catenins
Bone Morphogenetic Proteins
Protein Sorting Signals
Complement C1r
Neoplasms
Cytology
Molecular biology
Cell adhesion
Cell proliferation
Cadherins
Growth
Tumor Suppressor Genes
Heterografts
Nude Mice
Cell Adhesion

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Domain and functional analysis of a novel breast tumor suppressor protein, SCUBE2. / Lin, Yuh Charn; Chen, Chun Chuan; Cheng, Chien Jui; Yang, Ruey Bing.

In: Journal of Biological Chemistry, Vol. 286, No. 30, 29.07.2011, p. 27039-27047.

Research output: Contribution to journalArticle

Lin, Yuh Charn ; Chen, Chun Chuan ; Cheng, Chien Jui ; Yang, Ruey Bing. / Domain and functional analysis of a novel breast tumor suppressor protein, SCUBE2. In: Journal of Biological Chemistry. 2011 ; Vol. 286, No. 30. pp. 27039-27047.
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