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Reciprocal Signaling between the Transcriptional Co-Factor Eya2 and Specific Members of the Gi Family

Departments of Biochemistry (A.C.E., P.J.C.), Pharmacology & Cancer Biology (P.J.C.), Duke University Medical Center, Durham, North Carolina; Department of Pharmacology, University of Washington, Seattle, Washington (J.L.G.); and Department of Cell Biology and Physiology, Washington University, St. Louis, Missouri (M.E.L.)

As part of a program to elucidate signaling processes controlled by the heterotrimeric G protein Gz, a human fetal brain cDNA library was screened for proteins that specifically interact with the activated form of Gz. One of the most-encountered molecules in this screen was Eya2, a member of the Eyes absent family of proteins. Mammalian Eya proteins are predominantly cytosolic proteins that are known to interact with members of the Sine oculis (Six) family of homeodomain transcription factors. This interaction facilitates the translocation of Eya into the nucleus, where the Eya/Six complex regulates transcription during critical stages of embryonic development. In vitro binding studies confirmed that Gz interacts with Eya2 in an activation-dependent fashion; furthermore, most other members of the Gi family including Gi1, Gi2, and Gi3 were found to interact with Eya2. It is interesting that one of the most abundant Gi proteins, Go, did not interact with Eya2. Coexpression of the activated forms of Gi1, Gi2, and Gi3, but not Go, with Eya2 recruited Eya2 to the plasma membrane, prevented Eya2 translocation into the nucleus, and abrogated Eya2/Six4-mediated transcription. In addition, Eya2 impinged on G protein-mediated signaling, as evidenced by its ability to relieve Gi2-mediated inhibition of adenylyl cyclase. These results demonstrate that the interaction between the Gi proteins and Eya2 may impact on seemingly disparate regulatory events involving both classes of proteins.

Received for publication June 21, 2004.

Accepted for publication August 12, 2004.

Address correspondence to: Dr. Patrick J. Casey, Department of Pharmacology and Cancer Biology, Duke University Medical Center, Box 3813, Durham, NC 27710-3813. E-mail: casey006{at}mc.duke.edu

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