Previous Article | Next Article 
Molecular and Cellular Biology, August 2001, p. 5346-5358, Vol. 21, No. 16
0270-7306/01/$04.00+0 DOI: 10.1128/MCB.21.16.5346-5358.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Antiapoptotic Signaling Generated by
Caspase-Induced Cleavage of RasGAP
Jiang-Yan
Yang1 and
Christian
Widmann1,2,*
Institut de Biologie Cellulaire et de
Morphologie, Université de Lausanne,1 and
Départment de Médecine Interne, Centre Hospitalier
Universitaire Vaudois,2 Lausanne, Switzerland
Received 21 December 2000/Returned for modification 2 February
2001/Accepted 9 May 2001
Activation of caspases 3 and 9 is thought to commit a cell
irreversibly to apoptosis. There are, however, several documented situations (e.g., during erythroblast differentiation) in which caspases are activated and caspase substrates are cleaved with no
associated apoptotic response. Why the cleavage of caspase substrates
leads to cell death in certain cases but not in others is unclear. One
possibility is that some caspase substrates generate antiapoptotic
signals when cleaved. Here we show that RasGAP is one such protein.
Caspases cleave RasGAP into a C-terminal fragment (fragment C) and an
N-terminal fragment (fragment N). Fragment C expressed alone induces
apoptosis, but this effect could be totally blocked by fragment N. Fragment N could also block apoptosis induced by low levels of caspase
9. As caspase activity increases, fragment N is further cleaved into
fragments N1 and N2. Apoptosis induced by high levels of caspase 9 or
by cisplatin was strongly potentiated by fragment N1 or N2 but not by
fragment N. The present study supports a model in which RasGAP
functions as a sensor of caspase activity to determine whether or not a
cell should survive. When caspases are mildly activated, the partial
cleavage of RasGAP protects cells from apoptosis. When caspase activity
reaches levels that allow completion of RasGAP cleavage, the resulting
RasGAP fragments turn into potent proapoptotic molecules.
*
Corresponding author. Mailing address: Institut de
Biologie Cellulaire et de Morphologie, University of Lausanne, rue du
Bugnon 9, 1005 Lausanne, Switzerland. Phone: 41 21 92 5123. Fax: 41 21 692 5255. E-mail: Christian.Widmann{at}ibcm.unil.ch.
Molecular and Cellular Biology, August 2001, p. 5346-5358, Vol. 21, No. 16
0270-7306/01/$04.00+0 DOI: 10.1128/MCB.21.16.5346-5358.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
This article has been cited by other articles:
-
Dobkin-Bekman, M., Naidich, M., Rahamim, L., Przedecki, F., Almog, T., Lim, S., Melamed, P., Liu, P., Wohland, T., Yao, Z., Seger, R., Naor, Z.
(2009). A Preformed Signaling Complex Mediates GnRH-Activated ERK Phosphorylation of Paxillin and FAK at Focal Adhesions in L{beta}T2 Gonadotrope Cells. Mol. Endocrinol.
23: 1850-1864
[Abstract]
[Full Text]
-
Yang, J.-Y., Walicki, J., Jaccard, E., Dubuis, G., Bulat, N., Hornung, J.-P., Thorens, B., Widmann, C.
(2009). Expression of the NH2-Terminal Fragment of RasGAP in Pancreatic {beta}-Cells Increases Their Resistance to Stresses and Protects Mice From Diabetes. Diabetes
58: 2596-2606
[Abstract]
[Full Text]
-
Cornu, M., Yang, J.-Y., Jaccard, E., Poussin, C., Widmann, C., Thorens, B.
(2009). Glucagon-Like Peptide-1 Protects {beta}-Cells Against Apoptosis by Increasing the Activity of an Igf-2/Igf-1 Receptor Autocrine Loop. Diabetes
58: 1816-1825
[Abstract]
[Full Text]
-
Michod, D., Annibaldi, A., Schaefer, S., Dapples, C., Rochat, B., Widmann, C.
(2009). Effect of RasGAP N2 Fragment-Derived Peptide on Tumor Growth in Mice. JNCI J Natl Cancer Inst
101: 828-832
[Abstract]
[Full Text]
-
Chen, C.-N. N., Chen, H.-R., Yeh, S.-Y., Vittore, G., Ho, T.-H. D.
(2009). Autophagy Is Enhanced and Floral Development Is Impaired in AtHVA22d RNA Interference Arabidopsis. Plant Physiol.
149: 1679-1689
[Abstract]
[Full Text]
-
Bulat, N., Waeber, G., Widmann, C.
(2009). LDLs stimulate p38 MAPKs and wound healing through SR-BI independently of Ras and PI3 kinase. J. Lipid Res.
50: 81-89
[Abstract]
[Full Text]
-
Lin, H., Goodenough, U. W.
(2007). Gametogenesis in the Chlamydomonas reinhardtii minus Mating Type Is Controlled by Two Genes, MID and MTD1. Genetics
176: 913-925
[Abstract]
[Full Text]
-
Michod, D., Widmann, C.
(2007). TAT-RasGAP317-326 Requires p53 and PUMA to Sensitize Tumor Cells to Genotoxins. Mol Cancer Res
5: 497-507
[Abstract]
[Full Text]
-
Fernando, P., Megeney, L. A.
(2007). Is caspase-dependent apoptosis only cell differentiation taken to the extreme?. FASEB J.
21: 8-17
[Abstract]
[Full Text]
-
Zhao, X., Wang, D., Zhao, Z., Xiao, Y., Sengupta, S., Xiao, Y., Zhang, R., Lauber, K., Wesselborg, S., Feng, L., Rose, T. M., Shen, Y., Zhang, J., Prestwich, G., Xu, Y.
(2006). Caspase-3-dependent Activation of Calcium-independent Phospholipase A2 Enhances Cell Migration in Non-apoptotic Ovarian Cancer Cells. J. Biol. Chem.
281: 29357-29368
[Abstract]
[Full Text]
-
Yang, J.-Y., Walicki, J., Abderrahmani, A., Cornu, M., Waeber, G., Thorens, B., Widmann, C.
(2005). Expression of an Uncleavable N-terminal RasGAP Fragment in Insulin-secreting Cells Increases Their Resistance toward Apoptotic Stimuli without Affecting Their Glucose-induced Insulin Secretion. J. Biol. Chem.
280: 32835-32842
[Abstract]
[Full Text]
-
Yang, J.-Y., Walicki, J., Michod, D., Dubuis, G., Widmann, C.
(2005). Impaired Akt Activity Down-Modulation, Caspase-3 Activation, and Apoptosis in Cells Expressing a Caspase-resistant Mutant of RasGAP at Position 157. Mol. Biol. Cell
16: 3511-3520
[Abstract]
[Full Text]
-
Lypowy, J., Chen, I.-Y., Abdellatif, M.
(2005). An Alliance between Ras GTPase-activating Protein, Filamin C, and Ras GTPase-activating Protein SH3 Domain-binding Protein Regulates Myocyte Growth. J. Biol. Chem.
280: 25717-25728
[Abstract]
[Full Text]
-
Yang, J.-Y., Michod, D., Walicki, J., Murphy, B. M., Kasibhatla, S., Martin, S. J., Widmann, C.
(2004). Partial Cleavage of RasGAP by Caspases Is Required for Cell Survival in Mild Stress Conditions. Mol. Cell. Biol.
24: 10425-10436
[Abstract]
[Full Text]
-
Bartling, B., Yang, J.-Y., Michod, D., Widmann, C., Lewensohn, R., Zhivotovsky, B.
(2004). RasGTPase-activating protein is a target of caspases in spontaneous apoptosis of lung carcinoma cells and in response to etoposide. Carcinogenesis
25: 909-921
[Abstract]
[Full Text]
-
Yue, Y., Lypowy, J., Hedhli, N., Abdellatif, M.
(2004). Ras GTPase-activating Protein Binds to Akt and Is Required for Its Activation. J. Biol. Chem.
279: 12883-12889
[Abstract]
[Full Text]
-
Dobreva, I., Waeber, G., Mooser, V., James, R. W., Widmann, C.
(2003). LDLs induce fibroblast spreading independently of the LDL receptor via activation of the p38 MAPK pathway. J. Lipid Res.
44: 2382-2390
[Abstract]
[Full Text]
-
Sordet, O., Rebe, C., Plenchette, S., Zermati, Y., Hermine, O., Vainchenker, W., Garrido, C., Solary, E., Dubrez-Daloz, L.
(2002). Specific involvement of caspases in the differentiation of monocytes into macrophages. Blood
100: 4446-4453
[Abstract]
[Full Text]
-
Gigoux, V., L'Hoste, S., Raynaud, F., Camonis, J., Garbay, C.
(2002). Identification of Aurora Kinases as RasGAP Src Homology 3 Domain-binding Proteins. J. Biol. Chem.
277: 23742-23746
[Abstract]
[Full Text]
-
Yang, J.-Y., Widmann, C.
(2002). The RasGAP N-terminal Fragment Generated by Caspase Cleavage Protects Cells in a Ras/PI3K/Akt-dependent Manner That Does Not Rely on NFkappa B Activation. J. Biol. Chem.
277: 14641-14646
[Abstract]
[Full Text]
-
Schlesinger, T. K., Bonvin, C., Jarpe, M. B., Fanger, G. R., Cardinaux, J.-R., Johnson, G. L., Widmann, C.
(2002). Apoptosis Stimulated by the 91-kDa Caspase Cleavage MEKK1 Fragment Requires Translocation to Soluble Cellular Compartments. J. Biol. Chem.
277: 10283-10291
[Abstract]
[Full Text]