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Molecular and Cellular Biology, January 2000, p. 684-696, Vol. 20, No. 2
0270-7306/0/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Caspase 3 Cleavage of the Ste20-Related Kinase SLK Releases and Activates an Apoptosis-Inducing Kinase Domain and an Actin-Disassembling Region

Luc A. Sabourin,1 Patrick Seale,1,2 Julian Wagner,1 and Michael A. Rudnicki1,*

Institute for Molecular Biology and Biotechnology1 and Department of Biology,2 McMaster University, Hamilton, Ontario, Canada

Received 4 May 1999/Returned for modification 15 June 1999/Accepted 27 September 1999

We have demonstrated that a novel Ste20-related kinase, designated SLK, mediates apoptosis and actin stress fiber dissolution through distinct domains generated by caspase 3 cleavage. Overexpression of SLK in C2C12 myoblasts stimulated the disassembly of actin stress fibers and focal adhesions and induced apoptosis, as determined by annexin V binding and terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling analysis. SLK was cleaved by caspase 3 in vitro and in vivo during c-Myc-, tumor necrosis factor alpha, and UV-induced apoptosis. Furthermore, cleavage of SLK released two domains with distinct activities: an activated N-terminal kinase domain that promoted apoptosis and cytoskeletal rearrangements and a C-terminus domain that disassembled actin stress fibers. Moreover, our analysis has identified a novel conserved region (termed the AT1-46 homology domain) that efficiently promotes stress fiber disassembly. Finally, transient transfection of SLK also activated the c-Jun N-terminal kinase signaling pathway. Our results suggest that caspase-activated SLK represents a novel effector of cytoskeletal remodeling and apoptosis.

* Corresponding author. Mailing address: MOBIX, Institute for Molecular Biology and Biotechnology, McMaster University, Life Science Bldg., Rm. 437, 1280 Main St. West, Hamilton, Ontario, Canada L8S 4K1. Phone: (905) 525-9140, ext. 27424. Fax: (905) 521-2955. E-mail: rudnicki{at}mcmaster.ca.

Molecular and Cellular Biology, January 2000, p. 684-696, Vol. 20, No. 2
0270-7306/0/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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