Mae mediates MAP kinase phosphorylation of Ets transcription factors in Drosophila

Abstract

The evolutionarily conserved Ras/mitogen-activated protein kinase (MAPK) cascade is an integral part of the processes of cell division, differentiation, movement and death. Signals received at the cell surface are relayed into the nucleus, where MAPK phosphorylates and thereby modulates the activities of a subset of transcription factors. Here we report the cloning and characterization of a new component of this signal transduction pathway called Mae (for modulator of the activity of Ets). Mae is a signalling intermediate that directly links the MAPK signalling pathway to its downstream transcription factor targets. Phosphorylation by MAPK of the critical serine residue (Ser 127) of the Drosophila transcription factor Yan depends on Mae, and is mediated by the binding of Yan to Mae through their Pointed domains. This phosphorylation is both necessary and sufficient to abrogate transcriptional repression by Yan. Mae also regulates the activity of the transcriptional activator Pointed-P2 by a similar mechanism. Mae is essential for the normal development and viability of Drosophila, and is required in vivo for normal signalling of the epidermal growth factor receptor. Our study indicates that MAPK signalling specificity may depend on proteins that couple specific substrates to the kinase.

A KSR/CNK complex mediated by HYP, a novel SAM domain-containing protein, regulates RAS-dependent RAF activation in Drosophila

“…Although the CNK/HYP-binding mode and its structural consequence allowing KSR binding have yet to be determined, our findings are intriguingly similar to the recruitment of Rolled/MAPK to YAN, a Drosophila SAM/PNT domaincontaining transcriptional repressor that is inactivated following its phosphorylation by MAPK (Rebay and Rubin 1995). In that particular case, the recruitment of MAPK to YAN depends on a short SAM domain protein, known as MAE, that heterodimerizes with the SAM domain of YAN (Baker et al 2001). …”

Three habits of highly effective signaling pathways: principles of transcriptional control by developmental cell signaling

“…In the absence of signaling, Yan mediates default repression of pathway target genes, whereas PntP2 is inactive. RTK/ Ras/MAPK signaling results in the phosphorylation of both transcription factors, inactivating Yan and stimulating PntP2, thus both derepressing and activating target gene expression (Brunner et al 1994;O'Neill et al 1994;Rebay and Rubin 1995;Gabay et al 1996;Flores et al 2000;Halfon et al 2000;Xu et al 2000;Baker et al 2001). The vertebrate Ets repressor protein ERF, which is excluded from the nucleus in response to Ras/MAPK signaling, may serve a function analogous to that of Yan (Mavrothalassitis and Ghysdael 2000).…”

EDL/MAE regulates EGF-mediated induction by antagonizing Ets transcription factor Pointed

“…We have identified a novel Ets-related factor EDL (ETS-domain lacking), containing the Pointed domain but not the ETS domain (Shilo, 1998), that may mediate this mechanism. EDL has also been identified as MAE (modulator of the activity of ETS), a protein that binds YAN and promotes its phosphorylation by MAPK (Baker et al, 2001). Although such activity suggests a role of EDL/MAE in the induced cells, we find that EDL/MAE is specifically expressed in cells that act as the induction center by producing Spitz EGF.…”