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Submitted on November 10, 2004
Accepted on December 13, 2004
2-macroglobulin via the c-Jun N-terminal protein kinase pathway*
From Population Council, New York, New York 10021
* To whom correspondence should be addressed. E-mail: Y-Cheng{at}popcbr.rockefeller.edu.
The blood-testis barrier (BTB) in the testis, in contrast to the blood-brain and blood-retina barriers, is composed of co-existing tight junctions (TJ) and basal ectoplasmic specializations (ES), a testis-specific type of adherens junction (AJ). Recent studies showed that BTB restructuring that facilitates germ cell migration involves proteolysis, an event that is usually restricted to the cell-matrix interface in other epithelia. For instance, a surge in 
2-macroglobulin (2-MG), a protease inhibitor produced by Sertoli cells, was detected at the Sertoli-Sertoli and Sertoli-germ cell interface in the epithelium during cadmium chloride (CdCl2)-induced BTB disruption in adult rats. It is thus proposed that the increase in 2-MG is crucial for protecting the epithelium from unwanted proteolysis, as well as regulating the availability of cytokines that affect junction turnover. While both TJ and AJ dynamics at the BTB are regulated via the p38 MAPK signaling pathway, the mechanism(s) that regulates 2-MG is entirely unknown. In this study, we have shown that by administering dimethylaminopurine, a c-Jun N terminus protein kinase (JNK) inhibitor, to the testis, JNK activity was blocked specifically and 2-MG production was inhibited, worsening the CdCl2-induced damage to the epithelium. Studies coupled with inhibitors, immunoblottings, immunofluorescent and electron microscopy have unequivocally demonstrated that the JNK signaling pathway is a putative regulatory pathway for 2-MG production in the testis. This finding illustrates for the first time that a cell-matrix restructuring event occurs in normal cell physiology at the cell-cell interface in the testis, highlighting the significance of 2-MG in the regulating of BTB function.
2-macroglobulin •
JNK
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