Abstract
The novel tumor biomarker MIEN1, identified by representational difference analysis, is overexpressed in breast cancer and prostate cancer. MIEN1 is considered an oncogenic protein, because MIEN1 overexpression functionally enhances migration and invasion of tumor cells via modulating the activity of AKT. However, the structure and molecular function of MIEN1 is little understood. Here, we report the solution structure of MIEN1, which adopts a thioredoxin-like fold with a redox-active motif. Comparison of backbone chemical shifts showed that most of the residues for both oxidized and reduced MIEN1 possessed the same backbone conformation, with differences limited to the active motif and regions in proximity. The redox potential of this disulfide bond was measured as −225 mV, which compares well with that of disulfides for other thioredoxin-like proteins. Overall, our results suggest that MIEN1 may have an important regulatory role in phosphorylation of AKT with its redox potential.
Highlights
Migration and invasion enhancer 1 (MIEN1), previously named C35/C17orf37, is a novel gene identified by representational difference analysis of breast tumor and normal cells [1]
Protein expression of MIEN1 was increased in patients with metastasis of breast cancer to lung and liver, which indicates that MIEN1 may be an important mediator of cancer cell metastasis [1,3]
The extent of secondary structural changes in MIEN1 at different pH values and temperature was measured by far-UV CD spectroscopy
Summary
Migration and invasion enhancer 1 (MIEN1), previously named C35/C17orf, is a novel gene identified by representational difference analysis of breast tumor and normal cells [1]. Analysis of its protein sequence revealed that MIEN1 contains a canonical immunoreceptor tyrosine-based activation motif, common in receptors of the immune system [5], which has been associated with cell transformation by activating downstream Syk signaling [6]. Geranylation of MIEN1 at the CAAX motif facilitated the association of the protein to the inner leaflet of plasma membrane, enhancing the migratory phenotype of cells by inducing increased filopodia formation and potentiating directional migration [8]. MIEN1 protein is a signaling molecule promoting cell migration and invasion through a PI3K/Akt pathway, thereby transcriptionally upregulating the NF-kB downstream target genes (matrix metlloprotease 9, urokinase plasminogen activator, and vascular endothelial growth factor) and resulting in cancer metastasis [3]. Little is known about the structural and functional relationship of MIEN1 to signaling
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