| Budget Amount *help |
¥3,300,000 (Direct Cost: ¥3,300,000)
Fiscal Year 2006: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 2005: ¥2,400,000 (Direct Cost: ¥2,400,000)
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| Research Abstract |
Ephrins function as ligands for Eph receptor protein tyrosine kinases in many physiological processes such as the development of the nervous system. Because ephrins are tethered to cell membrane, ephrins also have receptor-like activity and cause reverse signaling in response to the interaction with the cognate Eph receptors. However, we found that extracellular region of ephrin-B1 is secreted in the culture medium of some pancreas cancer cell lines, which is significantly stimulated by interaction with Eph receptor B2 (EphB2). While we investigated the mechanism of the cleavage of ephrin-B1 ectodomain, we observed that reverse signalling by ephrin-B1 promotes the invasive properties of cancer cells by regulating the secretion of matrix metalloproteinase-8 (MMP-8), which was the key enzyme of ephrin-B1 cleavage Ephrin-B1, a transmembrane protein, is often overexpressed in highly invasive tumours. We found that binding of EphB2 to ephrin-B1 expressed by pancreatic cancer cells promotes their secretion of MMP-8. This reverse signalling activity of ephrin-B1 requires its intracellular C terminus and involves the activation of Arf1 GTPase, a regulator of membrane trafficking. Furthermore, the promotion of pancreatic tumour cell invasion in vivo by ephrin-B1 also requires it to have an intact C terminus. Thus, we propose, the C terminus of ephrin-B1 regulates the invasive potential of cancer cells by stimulating the secretion of MMP-8. This then promotes extracellular matrix degradation, which is needed for invasion. Our results suggest that ephrin-B1 is a potential therapeutic target of cancers.
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