The Journal of Experimental Medicine
Torrey Pines Biolabs
  Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents
This Article
Right arrow Full Text
Right arrow Full Text (PDF, 426K)
Right arrow PPT slides of all figures
Right arrow Alert me when this article is cited
Right arrow Citation Map
Services
Right arrow Email this article
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new content in the JEM
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via CrossRef
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Levkau, B.
Right arrow Articles by Raines, E. W.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Levkau, B.
Right arrow Articles by Raines, E. W.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Facebook   Add to Reddit   Add to Technorati   Add to Twitter  
What's this?
© The Rockefeller University Press, 0022-1007/1998/2/579/ $5.00
The Journal of Experimental Medicine, Volume 187, Number 4, February 16, 1998 579-586

Articles

Caspase-mediated Cleavage of Focal Adhesion Kinase pp125FAK and Disassembly of Focal Adhesions in Human Endothelial Cell Apoptosis

Bodo Levkau*, Barbara Herren{ddagger}, Hidenori Koyama§, Russell Ross*, and Elaine W. Raines*

From the * Department of Pathology, University of Washington School of Medicine, Seattle, Washington 98195-7470; {ddagger} The Cruciform Project, The Wolfson Institute for Biomedical Research, University College London, London, United Kingdom WC1E 6JJ; and § Second Department of Internal Medicine, Osaka City University Medical School, Osaka, Japan 545

Normal endothelial and epithelial cells undergo apoptosis when cell adhesion and spreading are prevented, implying a requirement for antiapoptotic signals from the extracellular matrix for cell survival. We investigated some of the molecular changes occurring in focal adhesions during growth factor deprivation–induced apoptosis in confluent monolayers of human umbilical vein endothelial cells. Among the first morphologic changes after initiation of the apoptotic process are membrane blebbing, loss of focal adhesion sites, and retraction from the matrix followed by detachment. We observe a specific proteolytic cleavage of focal adhesion kinase (pp125FAK), an important component of the focal adhesion complex, and identify pp125FAK as a novel substrate for caspase-3 and caspase-3–like apoptotic caspases. The initial cleavage precedes detachment, and coincides with loss of pp125FAK and paxillin from focal adhesion sites and their redistribution into the characteristic membrane blebs of apoptotically dying cells. Cleavage of pp125FAK differentially affects its association with signaling and cytoskeletal components of the focal adhesion complex; binding of paxillin, but not pp130Cas (Cas, Crk-associated substrate) and vinculin, to the COOH terminally truncated pp125FAK is abolished. Therefore, caspase-mediated cleavage of pp125FAK may be participating in the disassembly of the focal adhesion complex and actively interrupting survival signals from the extracellular matrix, thus propagating the cell death program.

We would like to thank Bonnie Ashleman for technical assistance with the confocal microscopy, Drs. J. Thomas Parsons and Cheryl A. Borgman (University of Virginia, Charlottesville, VA) and Drs. Kim Orth and Vishva M. Dixit (University of Michigan, Ann Arbor, MI) for kindly providing reagents.

This work was supported in part by National Institutes of Health grant HL18645 to R. Ross and E.W. Raines. B. Levkau is a recipient of a training research scholarship by the Deutsche Forschungsgemeinschaft of Germany.

Address correspondence to Elaine W. Raines, University of Washington School of Medicine, Department of Pathology, Box 357470, J507, Seattle WA 98195-7470. Phone: 206-685-7441; Fax: 206-685-3018; E-mail: ewraines{at}u.washington.edu

1 Abbreviations used in this paper: Ac-DEVD-CHO, N-acetyl-Asp-Glu-Val-Asp-aldehyde; FAK, focal adhesion kinase; FRNK, pp125FAK-related nonkinase; GF, growth factor; HUVEC, human umbilical vein endothelial cell; PARP, poly(ADP-ribose) polymerase; PCNA, proliferating cell nuclear antigen; SH, Src homology domain; ZVAD-fmk, benzyloxycarbonyl-Val-Ala-Asp fluoromethyl ketone.


Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Facebook Facebook   Add to Reddit Reddit   Add to Technorati Technorati   Add to Twitter Twitter    What's this?


This article has been cited by other articles:



  Home | Help | Feedback | Subscriptions | Archive | Search
TABLE OF CONTENTS