Src-JNK Potentiation of Estrogen Receptor AF-1; Mechanism, and Role in Estrogen Action in Breast Cancer

摘要

Src tyrosine kinase activity is almost universally elevated and appears to play a role in breast cancer. Because estrogen receptor alpha (ERalpha) also plays a role, we examined the effect of elevated Src tyrosine kinase on ERalpha activities. Elevating Src activity leads to a dramatic increase in estrogen receptor transcriptional activation function 1 (AF-1), the hormone independent activation function in the receptor amino terminus. The increase in AF-1 proceeds by Src activation of two protein kinase cascades. One Src cascade leads to Ras, raf1, MEK, and the ERK type of MAP kinase. The second and major pathway leads to MEKK, JNKK, and the JNK type of MAP kinase. Whereas ERKs can activate the ER AF-1 directly at S118, some of the ERK activation and all of the JNK activation is S118 independent. These S118 independent effects are mediated by ERK and JNK phosphorylation of p16o coactivators which mediate AF-1 function. ERKs, activated either by Src or by EGF cascades, directly phosphorylate the p160 GRIP1 on Serine 736. Serine 515 is the major JNK target. Mutations of S515 eliminate Src-JNK activation of AF-1, whereas mutation of 5736 has a less pronounced but consistent effect on Src-ERK pathways. We conclude that elevated Src leads to elevation of ER AF-1 via elevation of p16o coactivator function. The knowledge of the molecular details of the Src - coactivator nexus may lead to new methods to interrupt Src action in breast cancer.