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Sphingosine kinase 1 isoform-specific interactions in breast cancer
Daniel Yagoub1, Marc R Wilkins, Angelina J Lay
1School of Biotechnology and Biomolecular Sciences (D.Y., M.R.W.), University of New South Wales, Sydney 2052, Australia; Centenary Institute (D.Y., A.L., D.G.K., P.X., E.M.M.), Sydney 2042, Australia; Translational Cancer Research Group (D.H., R.M.-W., E.M.M.), Faculty of Science, School of Medical and Molecular Biosciences, and Faculty of Engineering and Information Technology (S.B., G.H.), University of Technology Sydney, Sydney, New South Wales 2007, Australia; Department of Biochemistry (J.H.L., W.W.), Tufts University School of Medicine, Boston, Massachusetts 02111; Shanghai Medical School (P.X.), Fudan University, 200433 Shanghai, People's Republic of China; and Sydney Medical School (E.M.M.), The University of Sydney, Sydney 2006, Australia.
Abstract:
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, SK143 kDa and SK151 kDa, have been identified; however, the 51 kDa variant is predominant in breast cancer cells. No studies have investigated the protein-protein interactions of the 51 kDa 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 43 kDa 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 51 kDa 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.
Insights
This study identifies protein interactions for Sphingosine kinase 1 (SK1) isoforms, revealing isoform-specific partners that offer new insights into SK1
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Sphingosine kinase 1 (SK1) is a key signaling enzyme implicated in breast cancer progression and therapeutic resistance.
- SK1 exists in two main isoforms (43 kDa and 51 kDa), with the 51 kDa variant being predominant in breast cancer cells.
- Understanding the protein interactions of SK1 isoforms is crucial for elucidating its regulatory mechanisms and role in oncogenesis.
Purpose of the Study:
- To identify common and unique protein-protein interactions for both SK1 43 kDa and SK1 51 kDa isoforms.
- To investigate potential differences in protein interactions between the two SK1 isoforms.
- To gain insights into the molecular mechanisms underlying SK1-mediated oncogenicity in breast cancer.
Main Methods:
- Utilized a triple-labeling stable isotope labeling by amino acids in cell culture (SILAC) approach for quantitative proteomics.
- Performed SK1 immunoprecipitation followed by mass spectrometry to identify interacting proteins.
- Conducted a meta-analysis of multiple experimental replicates to generate a high-confidence list of protein interactions.
Main Results:
- Identified approximately 850 quantified proteins interacting with SK1, with a high-confidence list of 30 interactions per isoform.
- Discovered novel SK1 interaction partners, including supervillin and drebrin, supporting roles in cell migration, adhesion, and cytoskeletal remodeling.
- Revealed isoform-specific interactions: Protein phosphatase 2A exclusively interacted with SK1 43 kDa, while other proteins exclusively interacted with SK1 51 kDa.
Conclusions:
- Identified both common and isoform-specific protein interactors for SK1 43 kDa and SK1 51 kDa.
- The identified interactions provide novel insights into the regulation and function of SK1 isoforms in breast cancer.
- These findings contribute to understanding SK1-mediated oncogenicity and may inform the development of targeted therapies.
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