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PNAS 98 (7): 3690-3694

Copyright © 2001 by the National Academy of Sciences.


BIOLOGICAL SCIENCES / BIOCHEMISTRY

Akt phosphorylates and regulates the orphan nuclear receptor Nur77

Yuri Pekarsky*, Cora Hallas*, Alexey Palamarchuk*, Anatoliy Koval*, Florencia Bullrich*, Yoko Hirata{dagger}, Roberta Bichi*, Jean Letofsky*, and Carlo M. Croce*,{ddagger}

*Kimmel Cancer Institute, Thomas Jefferson University, 233 South 10th Street, Philadelphia, PA 19107; and {dagger}The Institute of Physical and Chemical Research, Nagoya 463-0003, Japan

Contributed by Carlo M. Croce

Accepted for publication January 2, 2001.

Abstract: The immediate early gene NUR77 (also called NGFI-B) is required for T cell antigen receptor-mediated cell death and is induced to very high levels in immature thymocytes and T cell hybridomas undergoing apoptosis. The Akt (PKB) kinase is a key player in transduction of anti-apoptotic and proliferative signals in T cells. Because Nur77 has a putative Akt phosphorylation site at Ser-350, and phosphorylation of this residue is critical for the transactivation activity of Nur77, we investigated whether Akt regulates Nur77. Coimmunoprecipitation experiments showed the detection of Nur77 in Akt immune complexes, suggesting that Nur77 and Akt physically interact. We further show that Akt specifically phosphorylates Ser-350 of the Nur77 protein within its DNA-binding domain in vitro and in vivo in 293 and NIH 3T3 cells. Because phosphorylation of Ser-350 of Nur77 is critical for its function as a transcription factor, we examined the effect of Akt on this function. By using luciferase assay experiments, we showed that phosphorylation of Nur77 by Akt decreased the transcriptional activity of Nur77 by 50–85%. Thus, we show that Akt interacts with Nur77 and inactivates Nur77 by phosphorylation at Ser-350 in a phosphatidylinositol 3-kinase-dependent manner, connecting the phosphatidylinositol 3-kinase-dependent Akt pathway and a nuclear receptor pathway.


{ddagger} To whom reprint requests should be addressed at: Kimmel Cancer Institute, 233 South 10th Street, BLSB Room 1050, Philadelphia, PA 19107. E-mail: Carlo.Croce{at}mail.tju.edu.

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