Proteinase-activated receptor 2 expression in breast cancer and its role in breast cancer cell migration.
Proteinase-activated receptor 2 (PAR2) is a G protein-coupled receptor that is activated by trypsin-like proteinases. PAR2 is detected in breast tumor specimens; however, it is not clear how PAR2 level in breast cancer cell/tissues compares with normal cell/tissues. Here, we show the elevation of PAR2 protein level in 76 of 105 breast tumor specimens but only 5 of 24 normal breast tissues. PAR2 level is also higher in breast cancer cell lines than that in normal breast cells and non-cancerous breast cell lines. To determine the role of PAR2 in breast carcinogenesis, we examined the effect of PAR2 agonists on cell proliferation and migration. Our studies show that PAR2 agonists (PAR2-activating peptide and trypsin) are neither potent growth enhancers nor chemoattractants to breast cancer cells. Instead, PAR2 agonists induce significant chemokinesis. PAR2-mediated chemokinesis is G(alphai)-dependent, and inhibiting Src kinase activity or silencing c-Src expression blocks PAR2-mediated chemokinesis. These results suggest that c-Src works downstream of G(alphai) to mediate this PAR2 agonist-induced event. To characterize c-Src effector, we reveal that PAR2 agonists activate JNKs in a Src-dependent manner and that JNK activity is essential for PAR2-mediated chemokinesis. Moreover, PAR2 agonist stimulation leads to paxillin Ser(178) phosphorylation and paxillin(S178A) mutant inhibits PAR2-mediated chemokinesis. In conclusion, our studies show that PAR2 agonists facilitate breast cancer cell chemokinesis through the G(alphai)-c-Src-JNK-paxillin signaling pathway.
Su
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S
Research Center for Traditional Chinese Medicine Complexity System, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Li
Y
Y
Luo
Y
Y
Sheng
Y
Y
Su
Y
Y
Padia
R N
RN
Pan
Z K
ZK
Dong
Z
Z
Huang
S
S
D001943:Breast Neoplasms / Q000473:pathology*; D000081247:CSK Tyrosine-Protein Kinase; D045744:Cell Line, Tumor; D002465:Cell Movement; D002633:Chemotaxis; D005260:Female; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000502:physiology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology; D051419:Paxillin / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000502:physiology; D044464:Receptor, PAR-2 / Q000819:agonists / Q000032:analysis / Q000502:physiology*; D015398:Signal Transduction; D014357:Trypsin / Q000494:pharmacology; D019061:src-Family Kinases
C496061:PXN protein, human; D051419:Paxillin; D011518:Proto-Oncogene Proteins; D044464:Receptor, PAR-2; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human; D048031:JNK Mitogen-Activated Protein Kinases; D014357:Trypsin; D019206:GTP-Binding Protein alpha Subunits, Gi-Go