Sphingosine Kinase 1 Isoform-Specific Interactions in Breast Cancer

Sphingosine kinase 1 (SK1) is a signaling enzyme that catalyzes the formation of sphingosine-1-phosphate. Overexpression of SK1 is causally associated with breast cancer progression and resistance to therapy. SK1 inhibitors are currently being investigated as promising breast cancer therapies. Two m...

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Bibliographic Details
Published in:Molecular endocrinology (Baltimore, Md.) Md.), 2014-11, Vol.28 (11), p.1899-1915
Main Authors: Yagoub, Daniel, Wilkins, Marc R, Lay, Angelina J, Kaczorowski, Dominik C, Hatoum, Diana, Bajan, Sarah, Hutvagner, Gyorgy, Lai, Jack H, Wu, Wengen, Martiniello-Wilks, Rosetta, Xia, Pu, McGowan, Eileen M
Format: Article
Language:English
Subjects:
Breast Neoplasms - metabolism
Cell Adhesion - physiology
Cell Line, Tumor
Cell Movement - physiology
Dipeptidyl-Peptidases and Tripeptidyl-Peptidases - metabolism
DNA-Binding Proteins - metabolism
Female
Humans
Latent TGF-beta Binding Proteins - metabolism
Lysophospholipids - metabolism
MCF-7 Cells
Original Research
Phosphotransferases (Alcohol Group Acceptor) - metabolism
Protein Isoforms - metabolism
Signal Transduction
Sphingosine - analogs & derivatives
Sphingosine - metabolism
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Summary:Sphingosine kinase 1 (SK1) is a signaling enzyme that catalyzes the formation of sphingosine-1-phosphate. Overexpression of SK1 is causally associated with breast cancer progression and resistance to therapy. SK1 inhibitors are currently being investigated as promising breast cancer therapies. Two major transcriptional isoforms, SK143kDa and SK151kDa, have been identified; however, the 51kDa variant is predominant in breast cancer cells. No studies have investigated the protein-protein interactions of the 51kDa isoform and whether the two SK1 isoforms differ significantly in their interactions. Seeking an understanding of the regulation and role of SK1, we used a triple-labeling stable isotope labeling by amino acids in cell culture-based approach to identify SK1-interacting proteins common and unique to both isoforms. Of approximately 850 quantified proteins in SK1 immunoprecipitates, a high-confidence list of 30 protein interactions with each SK1 isoform was generated via a meta-analysis of multiple experimental replicates. Many of the novel identified SK1 interaction partners such as supervillin, drebrin, and the myristoylated alanine-rich C-kinase substrate-related protein supported and highlighted previously implicated roles of SK1 in breast cancer cell migration, adhesion, and cytoskeletal remodeling. Of these interactions, several were found to be exclusive to the 43kDa isoform of SK1, including the protein phosphatase 2A, a previously identified SK1-interacting protein. Other proteins such as allograft inflammatory factor 1-like protein, the latent-transforming growth factor β-binding protein, and dipeptidyl peptidase 2 were found to associate exclusively with the 51kDa isoform of SK1. In this report, we have identified common and isoform-specific SK1-interacting partners that provide insight into the molecular mechanisms that drive SK1-mediated oncogenicity.
ISSN:0888-8809
1944-9917
DOI:10.1210/me.2013-1423