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Molecular and Cellular Biology, September 2007, p. 6038-6052, Vol. 27, No. 17
0270-7306/07/$08.00+0     doi:10.1128/MCB.00522-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Double Knockouts Reveal that Protein Tyrosine Phosphatase 1B Is a Physiological Target of Calpain-1 in Platelets{triangledown}

Shafi M. Kuchay,1 Nayoung Kim,1,2 Elizabeth A. Grunz,3 William P. Fay,3 and Athar H. Chishti1*

Department of Pharmacology, University of Illinois College of Medicine, Chicago, Illinois 60612,1 Department of Medicine, St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, Massachusetts 02135,2 Department of Internal Medicine, University of Missouri, Research Service, Harry S. Truman VAMC, Columbia, Missouri 652123

Received 26 March 2007/ Returned for modification 29 May 2007/ Accepted 8 June 2007

Calpains are ubiquitous calcium-regulated cysteine proteases that have been implicated in cytoskeletal organization, cell proliferation, apoptosis, cell motility, and hemostasis. Gene targeting was used to evaluate the physiological function of mouse calpain-1 and establish that its inactivation results in reduced platelet aggregation and clot retraction potentially by causing dephosphorylation of platelet proteins. Here, we report that calpain-1 null (Capn1–/–) platelets accumulate protein tyrosine phosphatase 1B (PTP1B), which correlates with enhanced tyrosine phosphatase activity and dephosphorylation of multiple substrates. Treatment of Capn1–/– platelets with bis(N,N-dimethylhydroxamido)hydroxooxovanadate, an inhibitor of tyrosine phosphatases, corrected the aggregation defect and recovered impaired clot retraction. More importantly, platelet aggregation, clot retraction, and tyrosine dephosphorylation defects were rescued in the double knockout mice lacking both calpain-1 and PTP1B. Further evaluation of mutant mice by the ferric chloride-induced arterial injury model suggests that the Capn1–/– mice are relatively resistant to thrombosis in vivo. Together, our results demonstrate that PTP1B is a physiological target of calpain-1 and suggest that a similar mechanism may regulate calpain-1-mediated tyrosine dephosphorylation in other cells.

* Corresponding author. Mailing address: Department of Pharmacology, UIC Cancer Center, University of Illinois at Chicago, 909 South Wolcott Avenue, Room 5097, Chicago, IL 60612-3725. Phone: (312) 355-1293. Fax: (312) 355-1297. E-mail: chishti{at}uic.edu

{triangledown} Published ahead of print on 18 June 2007.

Molecular and Cellular Biology, September 2007, p. 6038-6052, Vol. 27, No. 17
0270-7306/07/$08.00+0     doi:10.1128/MCB.00522-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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