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 O'Neill, G. M.
Right arrow Articles by Golemis, E. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by O'Neill, G. M.
Right arrow Articles by Golemis, E. A.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, August 2001, p. 5094-5108, Vol. 21, No. 15
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.15.5094-5108.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Proteolysis of the Docking Protein HEF1 and Implications for Focal Adhesion Dynamics

Geraldine M. O'Neill1,2 and Erica A. Golemis1,*

Division of Basic Science, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111,1 and Oncology Research Unit, The Children's Hospital at Westmead, Westmead, New South Wales 2145, Australia2

Received 26 October 2000/Returned for modification 11 December 2000/Accepted 9 May 2001

The dynamic regulation of focal adhesions is implicated in cellular processes of proliferation, differentiation, migration, and apoptosis. The focal adhesion-associated docking protein HEF1 is cleaved by caspases during both mitosis and apoptosis. Common to both of these cellular processes is the loss of focal adhesions, transiently during mitosis and permanently during apoptosis. The proteolytic processing of HEF1 during both mitosis and apoptosis therefore posits a general role for HEF1 as a sensor of altered adhesion states. In this study, we find that HEF1 undergoes proteolytic processing specifically in response to cellular detachment, while HEF1 proteolysis is prevented by specific integrin receptor ligation and focal adhesion formation. We show that overexpression of a C-terminal caspase-derived 28-kDa HEF1 peptide causes cellular rounding that is demonstrably separable from apoptosis. Mutation of the divergent helix-loop-helix motif found in 28-kDa HEF1 significantly reduces the induction of apoptosis by this peptide, while deletion of the amino-terminal 28 amino acids of 28-kDa HEF1 completely abrogates the induction of apoptosis. Conversely, these mutations have no effect on the rounding induced by 28-kDa HEF1. Finally, we detect a novel focal adhesion targeting domain located in the C terminus of HEF1 and show that this activity is necessary for HEF1-induced cell spreading. Together, these data suggest that proteolytic and other posttranslational modifications of HEF1 in response to loss of adhesion serve to modulate the disassembly of focal adhesions.

* Corresponding author. Mailing address: Fox Chase Cancer Center, 7701 Burholme Ave., Philadelphia, PA 19111. Phone: (215) 728- 2860. Fax: (215) 728-3616. E-mail: EA_Golemis{at}fccc.edu.

Molecular and Cellular Biology, August 2001, p. 5094-5108, Vol. 21, No. 15
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.15.5094-5108.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Izumchenko, E., Singh, M. K., Plotnikova, O. V., Tikhmyanova, N., Little, J. L., Serebriiskii, I. G., Seo, S., Kurokawa, M., Egleston, B. L., Klein-Szanto, A., Pugacheva, E. N., Hardy, R. R., Wolfson, M., Connolly, D. C., Golemis, E. A. (2009). NEDD9 Promotes Oncogenic Signaling in Mammary Tumor Development. Cancer Res. 69: 7198-7206 [Abstract] [Full Text]  
  • Singh, M. K., Dadke, D., Nicolas, E., Serebriiskii, I. G., Apostolou, S., Canutescu, A., Egleston, B. L., Golemis, E. A. (2008). A Novel Cas Family Member, HEPL, Regulates FAK and Cell Spreading. Mol. Biol. Cell 19: 1627-1636 [Abstract] [Full Text]  
  • Halle, M., Liu, Y.-C., Hardy, S., Theberge, J.-F., Blanchetot, C., Bourdeau, A., Meng, T.-C., Tremblay, M. L. (2007). Caspase-3 Regulates Catalytic Activity and Scaffolding Functions of the Protein Tyrosine Phosphatase PEST, a Novel Modulator of the Apoptotic Response. Mol. Cell. Biol. 27: 1172-1190 [Abstract] [Full Text]  
  • Dadke, D., Jarnik, M., Pugacheva, E. N., Singh, M. K., Golemis, E. A. (2006). Deregulation of HEF1 Impairs M-Phase Progression by Disrupting the RhoA Activation Cycle. Mol. Biol. Cell 17: 1204-1217 [Abstract] [Full Text]  
  • Zheng, M., McKeown-Longo, P. J. (2006). Cell adhesion regulates Ser/Thr phosphorylation and proteasomal degradation of HEF1. J. Cell Sci. 119: 96-103 [Abstract] [Full Text]  
  • Banno, T., Gazel, A., Blumenberg, M. (2005). Pathway-specific Profiling Identifies the NF-{kappa}B-dependent Tumor Necrosis Factor {alpha}-regulated Genes in Epidermal Keratinocytes. J. Biol. Chem. 280: 18973-18980 [Abstract] [Full Text]  
  • Einarson, M. B., Cukierman, E., Compton, D. A., Golemis, E. A. (2004). Human Enhancer of Invasion-Cluster, a Coiled-Coil Protein Required for Passage through Mitosis. Mol. Cell. Biol. 24: 3957-3971 [Abstract] [Full Text]  
  • Kim, W., Kook, S., Kim, D. J., Teodorof, C., Song, W. K. (2004). The 31-kDa Caspase-generated Cleavage Product of p130cas Functions as a Transcriptional Repressor of E2A in Apoptotic Cells. J. Biol. Chem. 279: 8333-8342 [Abstract] [Full Text]  
  • Riggins, R. B., Quilliam, L. A., Bouton, A. H. (2003). Synergistic Promotion of c-Src Activation and Cell Migration by Cas and AND-34/BCAR3. J. Biol. Chem. 278: 28264-28273 [Abstract] [Full Text]  
  • Vojtek, A. B., Taylor, J., DeRuiter, S. L., Yu, J.-Y., Figueroa, C., Kwok, R. P. S., Turner, D. L. (2003). Akt Regulates Basic Helix-Loop-Helix Transcription Factor-Coactivator Complex Formation and Activity during Neuronal Differentiation. Mol. Cell. Biol. 23: 4417-4427 [Abstract] [Full Text]  
  • Toby, G. G., Gherraby, W., Coleman, T. R., Golemis, E. A. (2003). A Novel RING Finger Protein, Human Enhancer of Invasion 10, Alters Mitotic Progression through Regulation of Cyclin B Levels. Mol. Cell. Biol. 23: 2109-2122 [Abstract] [Full Text]  
  • Cai, D., Felekkis, K. N., Near, R. I., O'Neill, G. M., van Seventer, J. M., Golemis, E. A., Lerner, A. (2003). The GDP Exchange Factor AND-34 Is Expressed in B Cells, Associates With HEF1, and Activates Cdc42. J. Immunol. 170: 969-978 [Abstract] [Full Text]  
  • Fashena, S. J., Einarson, M. B., O'Neill, G. M., Patriotis, C., Golemis, E. A. (2002). Dissection of HEF1-dependent functions in motility and transcriptional regulation. J. Cell Sci. 115: 99-111 [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»