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A more recent version of this article appeared on September 1, 2004
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Submitted on April 8, 2004
Revised on June 9, 2004
Accepted on June 17, 2004
, , 
, ,
*Department of Cell Biology, Section of Membrane Cell Biology, University of Groningen, Groningen, The Netherlands; and Institute for Clinical Chemistry and Laboratory Medicine, University of Regensburg, Regensburg, Germany
Monitoring Editor: Keith Mostov
Sphingoid bases have been implicated in various cellular processes including cell growth, apoptosis, and cell differentiation. Here, we show that the regulated turnover of sphingoid bases is crucial for cell polarity development, i.e., the biogenesis of apical plasma membrane domains, in well-differentiated hepatic cells. Thus, inhibition of dihydroceramide synthase or sphinganine kinase activity with fumonisin B1 or N,N-dimethylsphingosine, respectively, dramatically perturbs cell polarity development, which is due to increased levels of sphinganine. Consistently, reduction of free sphinganine levels stimulates cell polarity development. Moreover, dihydroceramide synthase, the predominant enzyme responsible for sphinganine turnover, is a target for cell polarity stimulating cAMP/PKA signaling cascades. Indeed, ESI-MS/MS analyses revealed a significant reduction in sphinganine levels in cAMP/PKA-stimulated cells. These data suggest that sphinganine turnover is critical for and is actively regulated during HepG2 cell polarity development. Previously, we have identified an apical plasma membrane directed trafficking pathway from the subapical compartment (SAC). This transport pathway, which is part of the basolateral-to-apical transcytotic itinerary, plays a crucial role in apical plasma membrane biogenesis. Here we show that, as a part of the underlying mechanism, the inhibition of dihydroceramide synthase activity and ensuing increased sphinganine levels specifically perturb the activation of this particular pathway in the de novo apical membrane biogenesis.
These authors contributed equally to this work.
Corresponding author. E-mail: s.c.d.van.ijzendoorn{at}med.rug.nl
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