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J. Biol. Chem., Vol. 281, Issue 2, 1001-1007, January 13, 2006

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Identification of a Switch in Neurotrophin Signaling by Selective Tyrosine Phosphorylation^*

Juan Carlos Arévalo1, Daniela B. Pereira2, Hiroko Yano, Kenneth K. Teng, and Moses V. Chao3

From the Molecular Neurobiology Program, Skirball Institute of Biomolecular Medicine, Departments of Cell Biology, Physiology and Neuroscience, New York University School of Medicine, New York, New York 10016 and the Department of Medicine, Weill Medical College of Cornell University, New York, New York 10021

Neurotrophins, such as nerve growth factor and brain-derived neurotrophic factor, activate Trk receptor tyrosine kinases through receptor dimerization at the cell surface followed by autophosphorylation and recruitment of intracellular signaling molecules. The intracellular pathways used by neurotrophins share many common protein substrates that are used by other receptor tyrosine kinases (RTK), such as Shc, Grb2, FRS2, and phospholipase C-. Here we describe a novel RTK mechanism that involves a 220-kilodalton membrane tetraspanning protein, ARMS/Kidins220, which is rapidly tyrosine phosphorylated in primary neurons after neurotrophin treatment. ARMS/Kidins220 undergoes multiple tyrosine phosphorylation events and also serine phosphorylation by protein kinase D. We have identified a single tyrosine (Tyr¹⁰⁹⁶) phosphorylation event in ARMS/Kidins220 that plays a critical role in neurotrophin signaling. A reassembled complex of ARMS/Kidins220 and CrkL, an upstream component of the C3G-Rap1-MAP kinase cascade, is SH3-dependent. However, Tyr¹⁰⁹⁶ phosphorylation enables ARMS/Kidins220 to recruit CrkL through its SH2 domain, thereby freeing the CrkL SH3 domain to engage C3G for MAP kinase activation in a neurotrophin dependent manner. Accordingly, mutation of Tyr¹⁰⁹⁶ abolished CrkL interaction and sustained MAPK kinase activity, a response that is not normally observed in other RTKs. Therefore, Trk receptor signaling involves an inducible switch mechanism through an unconventional substrate that distinguishes neurotrophin action from other growth factor receptors.

Received for publication, April 18, 2005 , and in revised form, October 7, 2005.

^* This work was supported in part by National Institutes of Health Grants NS21072, CA56490, and HD23315 (to M. V. C.). 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.

¹ Supported by a postdoctoral fellowship from the Spanish Ministry of Education and from a Laurie Deierlein/American Brain Tumor Association Fellowship.

² Supported by a postdoctoral fellowship from the Portuguese Foundation for Science and Technology.

³ To whom correspondence should be addressed: Skirball Inst. of Biomolecular Medicine, NYU School of Medicine, 540 First Ave., NY, NY 10016. Tel.: 212-263-0761; Fax: 212-263-0723; E-mail: chao{at}saturn.med.nyu.edu.

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