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J. Biol. Chem., Vol. 278, Issue 15, 13278-13285, April 11, 2003

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Phosphorylation of the Ras-GRF1 Exchange Factor at Ser^916/898 Reveals Activation of Ras Signaling in the Cerebral Cortex^*

Huibin Yang, Desma Cooley^§, Julie E. Legakis, Qingyuan Ge^¶, Rodrigo Andrade^**, and Raymond R. Mattingly^§§

From the Departments of  Pharmacology and ^** Psychiatry and Behavioral Neurosciences and the  Program in Molecular Biology and Genetics, Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, Michigan 48201 and ^¶ Cell Signaling Technology Inc., Beverly, Massachusetts 01915

The Ras-GRF1 exchange factor, which is regulated by increases in intracellular calcium and the release of G subunits from heterotrimeric G proteins, plays a critical role in the activation of neuronal Ras. Activation of G protein-coupled receptors stimulates an increase in the phosphorylation of Ras-GRF1 at certain serine residues. The first of these sites to be identified, Ser⁹¹⁶ in the mouse sequence (equivalent to Ser⁸⁹⁸ in the rat sequence), is required for full activation of the Ras exchange factor activity of Ras-GRF1 by muscarinic receptors. We demonstrate here that Ras-GRF1 is highly expressed in rat brain compared with the Sos exchange factor and that there is an increase in incorporation of ³²P into Ser⁸⁹⁸ of brain Ras-GRF1 following activation of protein kinase A. Phosphorylation of Ras-GRF1 at Ser⁹¹⁶ is also required for maximal induction of Ras-dependent neurite outgrowth in PC12 cells. A novel antibody (termed 2152) that selectively recognizes Ras-GRF1 when it is phosphorylated at Ser^916/898 confirmed the regulated phosphorylation of Ras-GRF1 by Western blotting in both model systems of transfected COS-7 and PC12 cells and also of the endogenous protein in rat forebrain slices. Indirect confocal immunofluorescence of transfected PC12 cells using antibody 2152 demonstrated reactivity only under conditions in which Ras-GRF1 was phosphorylated at Ser^916/898. Confocal immunofluorescence of cortical slices of rat brain revealed widespread and selective phosphorylation of Ras-GRF1 at Ser⁸⁹⁸. In the prefrontal cortex, there was striking phosphorylation of Ras-GRF1 in the dendritic tree, supporting a role for Ras activation and signal transduction in neurotransmission in this area.

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