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Grit, a GTPase-Activating Protein for the Rho Family, Regulates Neurite Extension through Association with the TrkA Receptor and N-Shc and CrkL/Crk Adapter Molecules

Takeshi Nakamura,^1,2,3, Misako Komiya,³ Kiyoaki Sone,¹ Eiji Hirose,¹ Noriko Gotoh,⁴ Hiroshi Morii,^1,2 Yasutaka Ohta,⁵ and Nozomu Mori^1,2*

Department of Molecular Genetics, National Institute for Longevity Sciences,¹ Program of Protecting the Brain, CREST, JST, Oobu, Aichi 474-8522,² Biomedical R&D Department, Sumitomo Electric Industries, Yokohama 244-8588, Japan,³ Department of Pharmacology and The Skirball Institute, New York University Medical School, New York, New York 10016,⁴ Hematology Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115⁵

Received 26 February 2002/ Returned for modification 17 April 2002/ Accepted 4 September 2002

Neurotrophins are key regulators of the fate and shape of neuronal cells and act as guidance cues for growth cones by remodeling the actin cytoskeleton. Actin dynamics is controlled by Rho GTPases. We identified a novel Rho GTPase-activating protein (Grit) for Rho/Rac/Cdc42 small GTPases. Grit was abundant in neuronal cells and directly interacted with TrkA, a high-affinity receptor for nerve growth factor (NGF). Another pool of Grit was recruited to the activated receptor tyrosine kinase through its binding to N-Shc and CrkL/Crk, adapter molecules downstream of activated receptor tyrosine kinases. Overexpression of the TrkA-binding region of Grit inhibited NGF-induced neurite elongation. Further, we found some tendency for neurite promotion in full-length Grit-overexpressing PC12 cells upon NGF stimulation. These results suggest that Grit, a novel TrkA-interacting protein, regulates neurite outgrowth by modulating the Rho family of small GTPases.

Present address: Department of Tumor Virology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan.

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