Eya protein phosphatase activity regulates Six1–Dach–Eya transcriptional effects in mammalian organogenesis

Abstract

The precise mechanistic relationship between gene activation and repression events is a central question in mammalian organogenesis, as exemplified by the evolutionarily conserved sine oculis (Six), eyes absent (Eya) and dachshund (Dach) network of genetically interacting proteins. Here, we report that Six1 is required for the development of murine kidney, muscle and inner ear, and that it exhibits synergistic genetic interactions with Eya factors. We demonstrate that the Eya family has a protein phosphatase function, and that its enzymatic activity is required for regulating genes encoding growth control and signalling molecules, modulating precursor cell proliferation. The phosphatase function of Eya switches the function of Six1-Dach from repression to activation, causing transcriptional activation through recruitment of co-activators. The gene-specific recruitment of a co-activator with intrinsic phosphatase activity provides a molecular mechanism for activation of specific gene targets, including those regulating precursor cell proliferation and survival in mammalian organogenesis.

Xeya3 regulates survival and proliferation of neural progenitor cells within the anterior neural plate of Xenopus embryos

“…It has been reported recently that members of the Eyes absent protein family exhibit a serine-/thyrosinephosphatase activity (Li et al, 2003;Rayapureddi et al, 2003;Tootle et al, 2003). The phosphatase domain is characterized by two conserved motives (WDLDETI and IGDGRDEE) within the highly conserved Eya domain at the C-terminus (Fig.…”

“…Instead, EYA proteins can physically interact by means of the so-called Eya domain at the C-terminus with dac and so and are thereby considered to regulate transcription of target genes in the context of a multimeric complex (Heanue et al, 1999;Ikeda et al, 2002;Silver et al, 2003;Ozaki et al, 2004). Recently, it has been demonstrated that Eya proteins translocate from the cytoplasm to the nucleus upon phosphorylation of a conserved PXS/TP motif by MAPK (Ohto et al, 1999;Hsiao et al, 2001) and harbor a phosphatase activity (Li et al, 2003;Rayapureddi et al, 2003;Tootle et al, 2003).…”

How to make a teleost adenohypophysis: Molecular pathways of pituitary development in zebrafish

“…Eya1 protein carries an intrinsic tyrosine phosphatase activity, which converts the complex from a transcriptional repressor to an activator (Li et al, 2003). In the developing zebrafish AH, six1 and eya1 are coexpressed in all cells and from earliest ppe stages onwards .…”

Cell cycle regulation of the human Six1 homeoprotein is mediated by APCCdh1

“…(Li et al, 2003;Zheng et al, 2003;Ozaki et al, 2004). Gene amplification and overexpression of Six1 is observed in human cancers, where it confers developmental properties on adult cells leading to an increase in both proliferation and metastasis (Li et al, 2002;Coletta et al, 2004;Reichenberger et al, 2005;Yu et al, 2006).…”