Translocation of sphingosine kinase 1 to the plasma membrane is mediated by calcium- and integrin-binding protein 1.
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 Ca(2+)-dependent manner at the previously identified "calmodulin-binding site" of SK1. We also demonstrate that CIB1 functions as a Ca(2+)-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.
Jarman
Kate E
KE
Centre for Cancer Biology, SA Pathology, Frome Road, Adelaide, South Australia, Australia.
Moretti
Paul A B
PA
Zebol
Julia R
JR
Pitson
Stuart M
SM
D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D002147:Calmodulin / Q000378:metabolism; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000201:enzymology*; D055785:Gene Knockdown Techniques; D005799:Genes, Dominant / Q000235:genetics; D006801:Humans; D019814:Myristic Acid / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D000099157:Sphingosine Kinase
D002118:Calcium; D002135:Calcium-Binding Proteins; D002147:Calmodulin; D019814:Myristic Acid; D016328:NF-kappa B; D017853:Phosphotransferases (Alcohol Group Acceptor); D014409:Tumor Necrosis Factor-alpha; D000099157:Sphingosine Kinase; C109198:CIB1 protein, human