EphB4 Receptor Tyrosine Kinase in Prostate Cancer

摘要

EphB4 is a member of the Eph family of receptor tyrosine kinases that is widely expressed in many cancer cell types. High expression of EphB4 has been positively correlated with prostate cancer malignancy. On the other hand, EphB4 has also been shown to be downregulated in other types of cancer. It is unclear how this receptor may promote or suppress oncogenesis under different circumstances. One possibility would be the Eph receptors have oncogenic activity when ephrin stimulation is low or absent, whereas activation of downstream signaling by high levels of these ligands suppresses the malignant properties of prostate cancer cells. I have shown that ephrin-A1 stimulation of EphA2, another Eph receptor widely expressed in cancer, triggers inactivation of the anti-oncogenic Akt-mTOR pathway through crosstalk with a serine/threonine phosphatase. The resulting tumor-suppressing effects could be exploited for prostate cancer therapy if the responsible signaling pathways could be maintained for prolonged periods. However, ephrin stimulation also causes rapid degradation of the Eph receptors, which in turn terminates their anti-oncogenic activities. Therefore, understanding the mechanisms through which E3 ubiquitin ligases regulate Eph receptor stability will help potentiate the anti-oncogenic effects of Eph receptors. I have found that two E3 ubiquitin ligases, Cbl and RNF5, seems not to be major ubiquitin ligases responsible for regulating Eph receptor stability in PC3 prostate cancer cells. On the other hand, the E3 ubiquitin ligase complex Cul4B-DDB1-DCAF5 identified by mass spectrometry as a possible ephrin-A1/EphA2 binding partner, may regulate EphA2 stability. Preventing Eph receptor degradation, for example by inhibiting ubiquitin ligases, should enhance Eph receptor-dependent anti-oncogenic signaling and thus represents a promising strategy for the design of novel therapeutic strategies.