Translocation of Sphingosine Kinase 1 to the Plasma Membrane Is Mediated by Calcium- and Integrin-binding Protein 1

• Published in: The Journal of biological chemistry Vol. 285; no. 1; pp. 483 - 492
• Main Authors: Jarman, Kate E., Moretti, Paul A.B., Zebol, Julia R., Pitson, Stuart M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2010; American Society for Biochemistry and Molecular Biology
• Subjects: Apoptosis - drug effects; Binding Sites; Calcium - metabolism; Calcium-Binding Proteins - metabolism; Calcium/Binding Proteins; Calcium/Cellular Regulation; Calmodulin - metabolism; Cell Line, Tumor; Cell Membrane - drug effects; Cell Membrane - enzymology; Enzymes/Kinase; Enzymes/Lipid; Gene Knockdown Techniques; Genes, Dominant - genetics; Humans; Lipid/Sphingolipids; Mechanisms of Signal Transduction; Myristic Acid - metabolism; NF-kappa B - metabolism; Phosphotransferases (Alcohol Group Acceptor) - metabolism; Protein Binding - drug effects; Protein Transport - drug effects; Protein/Protein-Protein Interactions; Protein/Translocation; Tumor Necrosis Factor-alpha - pharmacology; Protein/Protein-Protein Interactions; Enzymes/Kinase; Enzymes/Lipid; Lipid/Sphingolipids; Calcium/Cellular Regulation; Calcium/Binding Proteins; Protein/Translocation
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M109.068395

SK1 (sphingosine kinase 1) plays an important role in many aspects of cellular regulation. Most notably, elevated cellular SK1 activity leads to increased cell proliferation, protection from apoptosis, and induction of neoplastic transformation. We have previously shown that translocation of SK1 from the cytoplasm to the plasma membrane is integral for oncogenesis mediated by this enzyme. The molecular mechanism mediating this translocation of SK1 has remained undefined. Here, we demonstrate a direct role for CIB1 (calcium and integrin-binding protein 1) in this process. We show that CIB1 interacts with SK1 in a Ca2+-dependent manner at the previously identified “calmodulin-binding site” of SK1. We also demonstrate that CIB1 functions as a Ca2+-myristoyl switch, providing a mechanism whereby it translocates SK1 to the plasma membrane. Both small interfering RNA knockdown of CIB1 and the use of a dominant-negative CIB1 we have generated prevent the agonist-dependent translocation of SK1. Furthermore, we demonstrate the requirement of CIB1-mediated translocation of SK1 in controlling cellular sphingosine 1-phosphate generation and associated anti-apoptotic signaling.