1. Division of Developmental Biology, Cincinnati Childrens Hospital Research Foundation, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA
2. Departments of Molecular and Human Genetics, Neuroscience and Program in Developmental Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA
3. Pathology, Neuroscience and Program in Developmental Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA
4. Ophthalmology, Neuroscience and Program in Developmental Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA

Correspondence to: Rashmi S. Hegde¹ Email: rashmi.hegde@cchmc.org

Abstract

The Eyes absent proteins are members of a conserved regulatory network implicated in the development of the eye, muscle, kidney and ear^{1, 2, 3, 4, 5, 6, 7}. Mutations in the Eyes absent genes have been associated with several congenital disorders including the multi-organ disease bronchio-oto-renal syndrome⁸, congenital cataracts⁹ and late-onset deafness¹⁰. On the basis of previous analyses it has been shown that Eyes absent is a nuclear transcription factor, acting through interaction with homeodomain-containing Sine oculis (also known as Six) proteins¹¹. Here we show that Eyes absent is also a protein tyrosine phosphatase. It does not resemble the classical tyrosine phosphatases that use cysteine as a nucleophile and proceed by means of a thiol-phosphate intermediate¹². Rather, Eyes absent is the prototype for a class of protein tyrosine phosphatases that use a nucleophilic aspartic acid in a metal-dependent reaction. Furthermore, the phosphatase activity of Eyes absent contributes to its ability to induce eye formation in Drosophila.