Abstract
Regulation of gene expression downstream of the Receptor Tyrosine Kinase signaling pathway in Drosophila relies on a transcriptional effector network featuring two conserved Ets family proteins, Yan and Pointed, known as TEL1 (ETV6) and ETS1/ETS2, respectively, in mammals. As in Drosophila, both TEL1 and ETS1/ETS2 operate as Ras pathway transcriptional effectors and misregulated activity of either factor has been implicated in many human leukemias and solid tumors. Providing essential regulation to the Drosophila network, direct interactions with the SAM domain protein Mae attenuate both Yan-mediated repression and PointedP2-mediated transcriptional activation. Given the critical contributions of Mae to the Drosophila circuitry, we investigated whether the human Ets factors TEL1 and ETS1/ETS2 could be subject to analogous regulation. Here we demonstrate that the SAM domain of human TEL2 can inhibit the transcriptional activities of ETS1/2 and TEL1. Drosophila Mae can also attenuate human ETS1/ETS2 function, suggesting there could be cross-species conservation of underlying mechanism. In contrast, Mae is not an effective inhibitor of TEL1, suggesting the mode of TEL2SAM-mediated inhibition of TEL1 may be distinct from how Drosophila Mae antagonizes Yan. Together our results reveal both further similarities and new differences between the mammalian and Drosophila networks and more broadly suggest that SAM domain-mediated interactions could provide an effective mechanism for modulating output from the TEL1 and ETS1/2 oncogenes.
Highlights
The evolutionarily conserved Receptor Tyrosine Kinase (RTK)/Ras/mitogen-activated protein kinase (MAPK) signal transduction cascade regulates such diverse processes as cell fate specification, proliferation, differentiation and survival [1]
TEL2SAM can inhibit transcriptional repression by TEL1 Considering the structural and functional similarities between the Yan and TEL1 repressors, together with the pivotal regulation provided by Modulator of activity of Ets (Mae) with respect to Yan, we speculated that a Maelike protein might regulate TEL1 activity
Of further interest is a splice isoform, TEL2a, that is predicted to encode a protein consisting of only the N-terminal Sterila Alpha Motif (SAM) domain [26], which would be structurally quite similar to Drosophila Mae
Summary
The evolutionarily conserved Receptor Tyrosine Kinase (RTK)/Ras/mitogen-activated protein kinase (MAPK) signal transduction cascade regulates such diverse processes as cell fate specification, proliferation, differentiation and survival [1]. Like its Drosophila counterpart Yan, TEL1 is a transcriptional repressor whose function is negatively regulated by ERK-mediated phosphorylation [11,12], while ETS1 and ETS2, like PntP2, are activators that require stimulation by dpERK (Figure 1A) [13].
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