This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Danilkovitch, A.
Right arrow Articles by Leonard, E. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Danilkovitch, A.
Right arrow Articles by Leonard, E. J.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, March 2000, p. 2218-2227, Vol. 20, No. 6
0270-7306/00/$04.00+0

Two Independent Signaling Pathways Mediate the Antiapoptotic Action of Macrophage-Stimulating Protein on Epithelial Cells

Alla Danilkovitch,* Shannon Donley, Alison Skeel, and Edward J. Leonard

Immunopathology Section, Laboratory of Immunobiology, National Cancer Institute, Frederick, Maryland

Received 31 August 1999/Returned for modification 6 October 1999/Accepted 7 December 1999

In addition to its effects on macrophage function, macrophage-stimulating protein (MSP) is a growth and motility factor for epithelial cells. The growth and survival of epithelial cells generally require two signals, one generated by interaction with extracellular matrix via integrins, the other initiated by a growth factor. Therefore we investigated the effect of MSP on epithelial cell survival. Survival of epithelial cells cultured overnight in serum-free medium was promoted by adhesion, which activated both the phosphatidylinositol 3'-kinase (PI3-K)/AKT and mitogen-activated protein kinase (MAPK) pathways, operating independently of one another. The number of apoptotic cells resulting from inhibition of either pathway alone was approximately doubled by simultaneous inhibition of both pathways. This shows that each pathway made a partial contribution to the prevention of apoptosis. In the presence of an inhibitor of either pathway, MSP increased the activity of the other pathway so that the single uninhibited pathway alone was sufficient to prevent apoptosis. In contrast to the results with adherent cells, although MSP also prevented apoptosis of cells in suspension (anoikis), its effect was mediated only by the PI3-K/AKT pathway. Despite activation of MAPK by MSP, anoikis was not prevented in suspended cells with a blocked PI3-K/AKT pathway. Thus, activation of MAPK alone is not sufficient to mediate MSP antiapoptotic effects. Cell adhesion generates an additional signal, which is essential for MSP to use MAPK in an antiapoptotic pathway. This may involve translocation of MSP-activated MAPK from the cytoplasm into the nucleus, which occurs only in adherent cells. Our results suggest that there is cross talk between cell matrix adhesion and growth factors in the regulation of cell survival via the MAPK pathway. Growth factors induce MAPK activation, and adhesion mediates MAPK translocation from the cytoplasm into the nucleus.

* Corresponding author. Mailing address: Bldg. 560/Rm 12-46, NCI-FCRDC, Frederick, MD 21702. Phone: (301) 846-1560. Fax: (301) 846-6145. E-mail: danilkovitch{at}mail.ncifcrf.gov.

Molecular and Cellular Biology, March 2000, p. 2218-2227, Vol. 20, No. 6
0270-7306/00/$04.00+0


This article has been cited by other articles:

  • Cantaluppi, V., Biancone, L., Romanazzi, G. M., Figliolini, F., Beltramo, S., Galimi, F., Camboni, M. G., Deriu, E., Conaldi, P., Bottelli, A., Orlandi, V., Herrera, M. B., Pacitti, A., Segoloni, G. P., Camussi, G. (2008). Macrophage Stimulating Protein May Promote Tubular Regeneration after Acute Injury. J. Am. Soc. Nephrol. 19: 1904-1918 [Abstract] [Full Text]  
  • Dominguez, F., Gadea, B., Esteban, F. J., Horcajadas, J. A., Pellicer, A., Simon, C. (2008). Comparative protein-profile analysis of implanted versus non-implanted human blastocysts. Hum Reprod 23: 1993-2000 [Abstract] [Full Text]  
  • Narasimhan, M., Ammanamanchi, S. (2008). Curcumin Blocks RON Tyrosine Kinase-Mediated Invasion of Breast Carcinoma Cells. Cancer Res. 68: 5185-5192 [Abstract] [Full Text]  
  • Zampieri, C. A., Fortin, J.-F., Nolan, G. P., Nabel, G. J. (2007). The ERK Mitogen-Activated Protein Kinase Pathway Contributes to Ebola Virus Glycoprotein-Induced Cytotoxicity. J. Virol. 81: 1230-1240 [Abstract] [Full Text]  
  • Matsuzaki, S., Canis, M., Pouly, J.L., Dechelotte, P., Okamura, K., Mage, G. (2005). The macrophage stimulating protein/RON system: a potential novel target for prevention and treatment of endometriosis. Mol Hum Reprod 11: 345-349 [Abstract] [Full Text]  
  • Peace, B. E., Toney-Earley, K., Collins, M. H., Waltz, S. E. (2005). Ron Receptor Signaling Augments Mammary Tumor Formation and Metastasis in a Murine Model of Breast Cancer. Cancer Res. 65: 1285-1293 [Abstract] [Full Text]  
  • Wang, D., Shen, Q., Xu, X.-M., Chen, Y.-Q., Wang, M.-H. (2005). Activation of the RON receptor tyrosine kinase attenuates transforming growth factor-{beta}1-induced apoptotic death and promotes phenotypic changes in mouse intestinal epithelial cells. Carcinogenesis 26: 27-36 [Abstract] [Full Text]  
  • Bijian, K., Takano, T., Papillon, J., Khadir, A., Cybulsky, A. V. (2004). Extracellular matrix regulates glomerular epithelial cell survival and proliferation. Am. J. Physiol. Renal Physiol. 286: F255-F266 [Abstract] [Full Text]  
  • Conner, S. R., Scott, G., Aplin, A. E. (2003). Adhesion-dependent Activation of the ERK1/2 Cascade Is By-passed in Melanoma Cells. J. Biol. Chem. 278: 34548-34554 [Abstract] [Full Text]  
  • Pankov, R., Cukierman, E., Clark, K., Matsumoto, K., Hahn, C., Poulin, B., Yamada, K. M. (2003). Specific beta 1 Integrin Site Selectively Regulates Akt/Protein Kinase B Signaling via Local Activation of Protein Phosphatase 2A. J. Biol. Chem. 278: 18671-18681 [Abstract] [Full Text]  
  • Danilkovitch-Miagkova, A., Duh, F.-M., Kuzmin, I., Angeloni, D., Liu, S.-L., Miller, A. D., Lerman, M. I. (2003). Hyaluronidase 2 negatively regulates RON receptor tyrosine kinase and mediates transformation of epithelial cells by jaagsiekte sheep retrovirus. Proc. Natl. Acad. Sci. USA 100: 4580-4585 [Abstract] [Full Text]  
  • Chen, Y.-Q., Zhou, Y.-Q., Fu, L.-H., Wang, D., Wang, M.-H. (2002). Multiple pulmonary adenomas in the lung of transgenic mice overexpressing the RON receptor tyrosine kinase. Carcinogenesis 23: 1811-1819 [Abstract] [Full Text]  
  • Schwartz, M. A., Assoian, R. K. (2002). Integrins and cell proliferation: regulation of cyclin-dependent kinases via cytoplasmic signaling pathways. J. Cell Sci. 114: 2553-2560 [Abstract] [Full Text]  
  • Rampino, T., Collesi, C., Gregorini, M., Maggio, M., Soccio, G., Guallini, P., Canton, A. D. (2002). Macrophage-Stimulating Protein Is Produced by Tubular Cells and Activates Mesangial Cells. J. Am. Soc. Nephrol. 13: 649-657 [Abstract] [Full Text]  
  • Aplin, A. E., Hogan, B. P., Tomeu, J., Juliano, R. L. (2002). Cell adhesion differentially regulates the nucleocytoplasmic distribution of active MAP kinases. J. Cell Sci. 115: 2781-2790 [Abstract] [Full Text]  
  • Danilkovitch-Miagkova, A., Miagkov, A., Skeel, A., Nakaigawa, N., Zbar, B., Leonard, E. J. (2001). Oncogenic Mutants of RON and MET Receptor Tyrosine Kinases Cause Activation of the {beta}-Catenin Pathway. Mol. Cell. Biol. 21: 5857-5868 [Abstract] [Full Text]  
  • Ballif, B. A., Blenis, J. (2001). Molecular Mechanisms Mediating Mammalian Mitogen-activated Protein Kinase (MAPK) Kinase (MEK)-MAPK Cell Survival Signals. Cell Growth Differ. 12: 397-408 [Full Text]  
  • Gauthier, R., Harnois, C., Drolet, J.-F., Reed, J. C., Vezina, A., Vachon, P. H. (2001). Human intestinal epithelial cell survival: differentiation state-specific control mechanisms. Am. J. Physiol. Cell Physiol. 280: C1540-C1554 [Abstract] [Full Text]  
  • Aplin, A. E., Stewart, S. A., Assoian, R. K., Juliano, R.L. (2001). Integrin-Mediated Adhesion Regulates ERK Nuclear Translocation and Phosphorylation of Elk-1. JCB 153: 273-282 [Abstract] [Full Text]  
  • Kang, K. W., Cho, M. K., Lee, C. H., Kim, S. G. (2001). Activation of Phosphatidylinositol 3-Kinase and Akt by tert-Butylhydroquinone Is Responsible for Antioxidant Response Element-Mediated rGSTA2 Induction in H4IIE Cells. Mol. Pharmacol. 59: 1147-1156 [Abstract] [Full Text]  
  • Danilkovitch-Miagkova, A., Angeloni, D., Skeel, A., Donley, S., Lerman, M., Leonard, E. J. (2000). Integrin-mediated RON Growth Factor Receptor Phosphorylation Requires Tyrosine Kinase Activity of Both the Receptor and c-Src. J. Biol. Chem. 275: 14783-14786 [Abstract] [Full Text]  
  • Aplin, A. E., Juliano, R.L. (2001). Regulation of nucleocytoplasmic trafficking by cell adhesion receptors and the cytoskeleton. JCB 155: 187-192 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»