How Golgi lipids drive growth factor signaling at the plasma membrane
Final Report Abstract
Triple-negative breast cancers (TNBCs) are especially refractory to treatment due to their negative hormone receptor and ErbB2/HER2 status. Therefore, the identification of cancer-associated deregulated signaling pathways is necessary to develop improved targeted therapies. In this project we revealed that the expression of the ceramide transfer protein CERT is reduced in TNBCs. CERT transfers ceramide from the endoplasmic reticulum to the Golgi complex for conversion into sphingomyelin (SM). We provide evidence that by regulating cellular SM levels, CERT determines the signaling output of the epidermal growth factor receptor (EGFR/ErbB1), which is upregulated in approximately 70% of TNBCs. CERT downregulation in breast cancer cells enhanced ErbB1 lateral mobility, ligand-induced autophosphorylation, internalization and chemotaxis. Together, our findings provide a link between lipid metabolism at the Golgi with signaling at the plasma membrane, thereby implicating CERT loss in the progression of TNBCs. Finally, considering that SM reduction compromises Fas/CD95 death receptor activation, CERT downregulation is likely to have a broad impact on cellular signalling characteristics, which are not restricted to the EGFR/ErbB1.
Publications
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(2012) Integration of non-vesicular and vesicular transport processes at the Golgi complex by the PKD-CERT network. Biochimica et biophysica acta, 1821, 1096-1103
Olayioye, M.A. and Hausser, A.
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(2012) Loss of the ceramide transfer protein augments EGF receptor signaling in breast cancer. Cancer research, 72, 2855-2866
Heering, J., Weis, N., Holeiter, M., Neugart, F., Staebler, A., Fehm, T.N., Bischoff, A., Schiller, J., Duss, S., Schmid, S., Korte, T., Herrmann, A. and Olayioye, M.A.
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(2013) PKD controls mitotic Golgi complex fragmentation through a Raf-MEK1 pathway. Molecular biology of the cell, 24, 222-233
Kienzle, C., Eisler, S.A., Villeneuve, J., Brummer, T., Olayioye, M.A. and Hausser, A.
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(2015) A computational model of PKD and CERT interactions at the trans-Golgi network of mammalian cells. BMC Systems Biology, 2015;9:9
Weber, P., Hornjik, M., Olayioye, M.A., Hausser, A. and Radde, N.
