MAE Fine-Tunes the Response

Abstract

The Drosophila Ets transcription factors Yan and pointed protein 2 (Pnt-P2) function antagonistically, downstream of receptor tyrosine kinase (RTK) signaling. Yan inhibits expression of target genes in undifferentiated cells. RTK activation of mitogen-activated protein kinase (MAPK) signaling leads to Yan phosphorylation and relieves Yan's transcriptional repression, allowing phosphorylated Pnt-P2 to activate this same set of genes, thereby promoting cell differentiation. Tootle et al. investigated the mechanisms by which MAPK regulates Yan and Pnt-P2 and uncovered a novel role for the protein modulator of the activity of Ets (MAE), which facilitates MAPK phosphorylation of Yan. Stimulating MAPK pathways with constitutively active Ras (Ras V12 ) in cultured Drosophila S2 cells led to export of Yan from the nucleus. Transgenic flies expressing Yan mutants that were not exported in response to MAPK signaling displayed phenotypes like those seen with constitutively active Yan. The authors used Yan deletion mutants to show that pointed domain (PD), a motif common to all three proteins that has been implicated in MAE binding to Yan and Pnt-P2, was necessary for regulation of Yan localization. Manipulation of mae expression in cells expressing Yan mutants indicated that MAE was required for export of Yan independently of its role in promoting Yan phosphorylation. MAE overexpression inhibited Yan-mediated transcriptional repression and, unexpectedly, inhibited Pnt-P2 transcriptional activation as well. The authors proposed that MAE participated in multiple steps in regulating Yan and Pnt-P2 activity to fine-tune the response to RTK signaling. T. L. Tootle, P. S. Lee, I. Rebay, CRM1-mediated nuclear export and regulated activity of the receptor tyrosine kinase antagonist YAN require specific interactions with MAE. Development 130 , 845-857 (2003). [Abstract] [Full Text]