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Molecular and Cellular Biology, March 2004, p. 1990-1999, Vol. 24, No. 5
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.5.1990-1999.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Persistent Signaling by Dysregulated Thrombin Receptor Trafficking Promotes Breast Carcinoma Cell Invasion

Michelle A. Booden,1 Lynn B. Eckert,1 Channing J. Der,1* and JoAnn Trejo1,2

Department of Pharmacology, Lineberger Comprehensive Cancer Center,1 Cardiovascular Biology Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 275992

Received 30 April 2003/ Returned for modification 6 May 2003/ Accepted 19 November 2003

Increased expression of protease-activated receptor 1 (PAR1), a G protein-coupled receptor for thrombin, has previously been correlated with breast carcinoma cell invasion. PAR1 is irreversibly proteolytically activated, internalized, and sorted directly to lysosomes, a critical process for the termination of signaling. We determined that activated PAR1 trafficking is severely altered in metastatic breast carcinoma cells but not in nonmetastatic or normal breast epithelial cells. Consequently, the proteolytically activated receptor is not sorted to lysosomes and degraded. Altered trafficking of proteolytically activated PAR1 caused sustained activation of phosphoinositide hydrolysis and extracellular signal-regulated kinase signaling, even after thrombin withdrawal, and enhanced cellular invasion. Thus, our results reveal that a novel alteration in trafficking of activated PAR1 causes persistent signaling and, in addition to other processes and proteins, contributes to breast carcinoma cell invasion.

* Corresponding author. Mailing address: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295. Phone: (919) 966-5634. Fax: (919) 966-0162. E-mail: cjder{at}med.unc.edu.

Molecular and Cellular Biology, March 2004, p. 1990-1999, Vol. 24, No. 5
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.5.1990-1999.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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