Journal
MOLECULAR AND CELLULAR BIOLOGY
Volume 24, Issue 5, Pages 1990-1999Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.24.5.1990-1999.2004
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Funding
- NCI NIH HHS [R01 CA092240, R01 CA063071, CA63071, CA92240] Funding Source: Medline
- NHLBI NIH HHS [K01 HL067697, HL67697] Funding Source: Medline
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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.
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