3. The CD95 two pathway model.

In 1998 the Peter lab demonstrated that caspase-8 has two ways to activate the downstream apoptosis machinery depending on the cell type (1,2). In Type I cells caspase-8 is activated at the death inducing signaling complex (DISC) in large quantities resulting in direct processing of caspase-3 (Figure). This step is independent of mitochondria and cannot be blocked by overexpression of Bcl-2. In Type II cells the amount of active caspase-8 generated at the DISC is very small. Apoptosis in Type II cells depends on the apoptogenic activity of mitochondria and is characterized by activation of large quantities of caspase-3 and caspase-8 downstream of the mitochondria. Only in these cells overexpression of Bcl-2 or Bcl-xL blocks activation of both caspases and apoptosis. Recently the Peter lab reported that CD95 clusters and internalizes in a caspase-8 and actin dependent fashion (3) and this activity is restricted to Type I cells (4). After years of controversy on the physiological function of CD95 ligand CD95L (5) the Peter lab demonstrated that the physiologic CD95 ligand is highly toxic to Type II cells but does not induce apoptosis on Type I cells (6). This allowed to type the 60 tumor cells of the NCI drug screening panel (NCI60) resulting in the discovery that Type I cells represent mesenchymal cells whereas Type II cells correspond to epithelial cells, respectively. It was also found that Type I and Type II tumor cells differ in their sensitivity to anti tumor drugs that target two major cytoskeleton systems. Type I cells are sensitive to all actin binding drugs whereas Type II cells are sensitive to tubulin binding drugs. These findings are relevant for activated T cells since it was previously shown that T cells differentiate from Type II to Type I during long-term T cell activation (7). Recent evidence suggest that the reason for the different signaling through CD95 in short-term versus long-term activated peripheral T-cells could be in the way the DISC is forming. Similar to the TNF-receptor I the DISC in Type II cells seems to form intracellularly (8). The Peter lab is currently studying the details of the signaling pathways in Type I and Type II cells.

 

References

1.	Scaffidi, C., Fulda, S., Srinivasan, A., Li, Feng, Friesen, C., Tomasseli, K.J.., Debatin, K.-M., Krammer, P.H. and Peter,M.E. (1998) Two CD95 (APO-1/Fas) signaling pathways. EMBO J., 17, 1675-1687. Highlighted in The Scientist as one of the hot papers of 1998: "Deconstructing Tumor Necrosis Factor". (2000) The Scientist 14:19.
2.	Barnhart B.C., Alappat, E., and Peter, M.E. (2003) CD95 Type I and Type II cells. Sem. Immunol., 15, 185-193.
3.	Algeciras-Schimnich, A., Shen, L., Barnhart, B.C., Murmann, A.E., Burkhardt, J and Peter,M.E. (2002) Molecular ordering of the initial signaling events of CD95. Mol. Cell. Biol., 22, 207-220.
4.	Algeciras-Schimnich A. and Peter,M.E. (2003) Actin dependent CD95 internalization is specific for Type I cells. FEBS Lett., 546, 185-188.
5.	Peter,M.E., Barnhart, B.C. and Algeciras-Schimnich, A. (2003) FasL/CD95L and its receptor CD95 (APO-1/Fas). in "Cytokine Handbook, 4th Edition. Ed. A. Thomson, M. Lotze. Academic press. Vol.2, pp. 885-911.
6.	Algeciras-Schimnich, A., Pietras, E., Barnhart, B.C., Legembre, P., Vijayan, S., Holbeck, S.L. and Peter,M.E. (2003) Two CD95 tumor classes with different sensitivites to antitumor drugs. Proc. Natl. Acad. Sci. USA, 100, 11445-11450.
7.	Scaffidi, C., Schmitz, I., Krammer, P.H. and Peter,M.E. (1999) Role of c-FLIP in modulation of CD95-induced apoptosis, J. Biol. Chem., 274, 1541-1548.
8.	Barnhart, B.C. and Peter,M.E. (2003) The TNF receptor 1: a split personality complex. Cell, 114, 148-150.