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J. Biol. Chem., Vol. 280, Issue 1, 225-235, January 7, 2005

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Neurotrophin-dependent Tyrosine Phosphorylation of Ras Guanine-releasing Factor 1 and Associated Neurite Outgrowth Is Dependent on the HIKE Domain of TrkA^*

Kim N. Robinson¶, Kara Manto, Rachel J. Buchsbaum||, James I. S. MacDonald, and Susan O. Meakin**

From the Laboratory of Neural Signaling, The Robarts Research Institute, London, Ontario N6A 5K8, Canada, the ^||Molecular Oncology Research Institute, Division of Hematology/Oncology, Tufts-New England Medical Center, Boston, Massachusetts, 02111, and the Graduate Program in Neuroscience and the ^**Department of Biochemistry, The University of Western Ontario, London, Ontario, N6A 5C1, Canada

Ras guanine-releasing factor 1 (RasGrf1), a guanine nucleotide exchange factor for members of the Ras and Rho family of GTPases, is highly expressed in the brain. It is regulated by two separate mechanisms, calcium regulation through interaction with its calcium/calmodulin-binding IQ domain and serine and tyrosine phosphorylation. RasGrf1 is activated downstream of G-protein-coupled receptors and the non-receptor tyrosine kinases, Src and Ack1. Previously, we demonstrated a novel interaction between the intracellular domain of the nerve growth factor-regulated TrkA receptor tyrosine kinase and an N-terminal fragment of RasGrf1. We now show that RasGrf1 is phosphorylated and interacts with TrkA, -B, and -C in co-transfection studies. This interaction and phosphorylation of RasGrf1 is dependent on the HIKE domain of TrkA (a region shown to interact with pleckstrin homology domains) but not on any of the phosphotyrosine residues that act as docking sites for intracellular signaling molecules such as Shc and FRS-2. The PH1 domain alone of RasGrf1 is sufficient for phosphorylation by the TrkA receptor. A potential role for Trk activation of RasGrf1 is suggested through transfection studies in PC12 cells in which RasGrf1 significantly increases neurite outgrowth at low doses of neurotrophin stimulation. Notably, this neurite outgrowth is dependent on an intact HIKE domain, as nnr5-S10 cells expressing a TrkA HIKE domain mutant do not exhibit potentiated neurite outgrowth in the presence of RasGrf1. These studies identify RasGrf1 as a novel target of neurotrophin activation and suggest an additional pathway whereby neurotrophin-stimulated neurite outgrowth may be regulated.

Received for publication, September 10, 2004 , and in revised form, October 26, 2004.

^* This work was supported with funds from an EJLB Foundation scholar research program grant and a Canadian Institutes of Health Research grant (to S. O. M.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ Recipient of an Ontario graduate scholarship in science and technology.

To whom correspondence should be addressed: Laboratory of Neural Signaling, The Robarts Research Inst., 100 Perth Dr., London, Ontario, N6A 5K8, Canada. Tel.: 519-663-5777 (ext. 34304); Fax: 519-663-3314; E-mail: smeakin{at}robarts.ca.

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