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A Multitasking Transcriptional Regulator

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Science's STKE  25 Nov 2003:
Vol. 2003, Issue 210, pp. tw456-TW456
DOI: 10.1126/stke.2102003TW456

A coregulatory protein called Eyes absent (Eya) is part of a conserved transcription network that controls development of the eye and other organs, including the kidney and ear. Presence of a motif at the C-terminus of Eya led three groups to discover that this regulatory protein harbors intrinsic protein phosphatase activity that may serve to dephosphorylate itself and other substrates to regulate gene expression. Biochemical analysis indicated that Eya is a type of haloacid dehalogenase (HAD) with enzymatic activity toward phosphotyrosine-containing peptide substrates in vitro. Transgenic flies expressing mutated forms of Eya lacking the HAD motif and phosphatase activity had abnormal eye development. Expression of the mutant forms was not able to rescue eye defects in flies harboring a defective eya gene. A transcription factor called Sine oculis (Six) interacts with Eya and Dachshund (Dach) to form activating or repressing transcriptional complexes, respectively. In cultured mammalian cells, the Dach-Six complex recruits corepressors to inhibit the expression of target genes such as c-myc. However, the recruitment of Eya to this complex stimulated the assembly of coactivators that promoted gene expression to support cell proliferation and survival. It remains unclear how Eya's phosphatase activity regulates its function.

X. Li, K. A. Oghi, J. Zhang, A. Krones, K. T. Bush, C. K. Glass, S. K. Nigam, A. K. Aggarwal, R. Mass, D. W. Rose, M. G. Rosenfeld, Eye protein phosphatase activity regulates Six1-Dach-Eya transcriptional effects in mammalian organogenesis. Nature 426, 247-254 (2003). [Online Journal]

J. P. Rayapureddi, C. Kattamuri, B. D. Steinmetz, B. J. Frankfort, E. J. Ostrin, G. Mardon, R. S. Hegde, Eyes absent represents a class of protein tyrosine phosphatases. Nature 426, 295-298 (2003). [Online Journal]

T. L. Tootle, S. J. Silver, E. L. Davies, V. Newman, R. R. Latek, I. A. Mills, J. D. Selengut, B. E. W. Parlikar, I. Rebay, The transcription factor Eyes absent is a protein tyrosine phosphatase. Nature 426, 299-302 (2003). [Online Journal]

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