BAD enables ceramide to signal apoptosis via Ras and Raf-1

J Biol Chem. 1998 Nov 13;273(46):30419-26. doi: 10.1074/jbc.273.46.30419.


Prior investigations document that proliferative signaling cascades, under some circumstances, initiate apoptosis, although mechanisms that dictate the final outcome are largely unknown. In COS-7 cells, ceramide signals Raf-1 activation through Ras (Zhang, Y., Yao, B., Delikat, S., Bayoumy, S., Lin, X. H., Basu, S., McGinley, M., Chan-Hui, P. Y., Lichenstein, H., and Kolesnick, R. (1997) Cell 89, 63-72), but not apoptosis. However, expression of small amounts of the pro-apoptotic Bcl-2 family member, BAD, conferred ceramide-induced apoptosis onto COS-7 cells. Ceramide signaled apoptosis in BAD-expressing cells by a pathway involving sequentially kinase suppressor of Ras (KSR)/ceramide-activated protein kinase, Ras, c-Raf-1, and MEK1. Downstream, this pathway linked to BAD dephosphorylation at serine 136 by prolonged inactivation of Akt/PKB. Further, mutation of BAD at serine 136 abrogated ceramide signaling of apoptosis. The present study indicates that when ceramide signals through the Ras/Raf cascade, the availability of a single target, BAD, may dictate an apoptotic outcome.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Apoptosis*
  • COS Cells
  • Carrier Proteins / physiology*
  • Ceramides / physiology*
  • Phosphorylation
  • Protein Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins c-raf / physiology*
  • Serine / metabolism
  • Signal Transduction*
  • bcl-Associated Death Protein
  • ras Proteins / physiology*


  • Carrier Proteins
  • Ceramides
  • Proto-Oncogene Proteins
  • bcl-Associated Death Protein
  • Serine
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins c-raf
  • ras Proteins