This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Lin, D. C.
Right arrow Articles by Kaplan, D. R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Lin, D. C.
Right arrow Articles by Kaplan, D. R.

 Previous Article  |  Next Article 

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.



This article has been cited by other articles:

  • Rashid, S., Pilecka, I., Torun, A., Olchowik, M., Bielinska, B., Miaczynska, M. (2009). Endosomal Adaptor Proteins APPL1 and APPL2 Are Novel Activators of {beta}-Catenin/TCF-mediated Transcription. J. Biol. Chem. 284: 18115-18128 [Abstract] [Full Text]  
  • Deepa, S. S., Dong, L. Q. (2009). APPL1: role in adiponectin signaling and beyond. Am. J. Physiol. Endocrinol. Metab. 296: E22-E36 [Abstract] [Full Text]  
  • McShane, M. P., Zerial, M. (2008). Survival of the weakest: signaling aided by endosomes. JCB 182: 823-825 [Abstract] [Full Text]  
  • Saito, T., Jones, C. C., Huang, S., Czech, M. P., Pilch, P. F. (2007). The Interaction of Akt with APPL1 Is Required for Insulin-stimulated Glut4 Translocation. J. Biol. Chem. 282: 32280-32287 [Abstract] [Full Text]  
  • Yi, Z., Petralia, R. S., Fu, Z., Swanwick, C. C., Wang, Y.-X., Prybylowski, K., Sans, N., Vicini, S., Wenthold, R. J. (2007). The Role of the PDZ Protein GIPC in Regulating NMDA Receptor Trafficking. J. Neurosci. 27: 11663-11675 [Abstract] [Full Text]  
  • Cheng, K. K.Y., Lam, K. S.L., Wang, Y., Huang, Y., Carling, D., Wu, D., Wong, C., Xu, A. (2007). Adiponectin-Induced Endothelial Nitric Oxide Synthase Activation and Nitric Oxide Production Are Mediated by APPL1 in Endothelial Cells. Diabetes 56: 1387-1394 [Abstract] [Full Text]  
  • Naska, S., Park, K. J., Hannigan, G. E., Dedhar, S., Miller, F. D., Kaplan, D. R. (2006). An Essential Role for the Integrin-Linked Kinase-Glycogen Synthase Kinase-3{beta} Pathway during Dendrite Initiation and Growth. J. Neurosci. 26: 13344-13356 [Abstract] [Full Text]  
  • Varsano, T., Dong, M.-Q., Niesman, I., Gacula, H., Lou, X., Ma, T., Testa, J. R., Yates, J. R. III, Farquhar, M. G. (2006). GIPC Is Recruited by APPL to Peripheral TrkA Endosomes and Regulates TrkA Trafficking and Signaling. Mol. Cell. Biol. 26: 8942-8952 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»