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Molecular and Cellular Biology, December 2006, p. 8928-8941, Vol. 26, No. 23
0270-7306/06/$08.00+0     doi:10.1128/MCB.00228-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

APPL1 Associates with TrkA and GIPC1 and Is Required for Nerve Growth Factor-Mediated Signal Transduction{triangledown}

Dan C. Lin,1 Celia Quevedo,1 Natalie E. Brewer,2 Alex Bell,3 Joseph R. Testa,4 Mark L. Grimes,5 Freda D. Miller,1,6 and David R. Kaplan1,6*

Cancer Research Program and Developmental Biology Program, Hospital for Sick Children, Toronto M5G 1X8, Ontario, Canada,1 Department of Neurology and Neurosurgery, McGill University, Montreal H3A 2B4, Quebec, Canada,2 Department of Anatomy and Cell Biology, McGill University, Montreal H3A 2B2, Quebec, Canada,3 Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, Pennsylvania 19111,4 Division of Biological Sciences, University of Montana, Missoula, Montana 59812-4824,5 Department of Medical Genetics and Microbiology, University of Toronto, Toronto M5S 1A8, Ontario, Canada6

Received 7 February 2006/ Returned for modification 28 March 2006/ Accepted 3 September 2006

The neurotrophin receptor TrkA plays critical roles in the nervous system by recruiting signaling molecules that activate pathways required for the growth and survival of neurons. Here, we report APPL1 as a TrkA-associated protein. APPL1 and TrkA coimmunoprecipitated in sympathetic neurons. We have identified two routes through which this association can occur. APPL1 was isolated as a binding partner for the TrkA-interacting protein GIPC1 from rat brain lysate by mass spectrometry. The PDZ domain of GIPC1 directly engaged the C-terminal sequence of APPL1. This interaction provides a means through which APPL1 may be recruited to TrkA. In addition, the APPL1 PTB domain bound to TrkA, indicating that APPL1 may associate with TrkA independently of GIPC1. Isolation of endosomal fractions by high-resolution centrifugation determined that APPL1, GIPC1, and phosphorylated TrkA are enriched in the same fractions. Reduction of APPL1 or GIPC1 protein levels suppressed nerve growth factor (NGF)-dependent MEK, extracellular signal-regulated kinase, and Akt activation and neurite outgrowth in PC12 cells. Together, these results indicate that GIPC1 and APPL1 play a role in TrkA function and suggest that a population of endosomes bearing a complex of APPL1, GIPC1, and activated TrkA may transmit NGF signals.

* Corresponding author. Mailing address: Cancer Research Program, Hospital for Sick Children, 555 University Ave., Toronto M5G 1X8, Ontario, Canada. Phone: (416) 813-7654, ext. 1433. Fax: (416) 813-2212. E-mail: dkaplan{at}sickkids.ca.

{triangledown} Published ahead of print on 25 September 2006.

Molecular and Cellular Biology, December 2006, p. 8928-8941, Vol. 26, No. 23
0270-7306/06/$08.00+0     doi:10.1128/MCB.00228-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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