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 Wong, A.
Right arrow Articles by Pachnis, V.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Wong, A.
Right arrow Articles by Pachnis, V.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, November 2005, p. 9661-9673, Vol. 25, No. 21
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.21.9661-9673.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Phosphotyrosine 1062 Is Critical for the In Vivo Activity of the Ret9 Receptor Tyrosine Kinase Isoform

Adrianne Wong,1,{dagger} Silvia Bogni,2,{dagger} Pille Kotka,1,{ddagger} Esther de Graaff,2,§ Vivette D'Agati,3 Frank Costantini,1,¶* and Vassilis Pachnis2,¶*

Department of Genetics and Development, Columbia University Medical Center, 701 W. 168th Street, New York, New York 10032,1 Division of Molecular Neurobiology, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, United Kingdom,2 Department of Pathology, Columbia University Medical Center, 630 W. 168th Street, New York, New York 100323

Received 23 May 2005/ Returned for modification 18 June 2005/ Accepted 2 July 2005

The receptor tyrosine kinase Ret plays a critical role in the development of the mammalian excretory and enteric nervous systems. Differential splicing of the primary Ret transcript results in the generation of two main isoforms, Ret9 and Ret51, whose C-terminal amino acid tails diverge after tyrosine (Y) 1062. Monoisoformic mice expressing only Ret9 develop normally and are healthy and fertile. In contrast, animals expressing only Ret51 have aganglionosis of the distal gut and hypoplastic kidneys. By generating monoisoformic mice in which Y1062 of Ret9 has been mutated to phenylalanine, we demonstrate that this amino acid has a critical role in Ret9 signaling that is necessary for the development of the kidneys and the enteric nervous system. These findings argue that the distinct activities of Ret9 and Ret51 result from the differential regulation of Y1062 by C-terminal flanking sequences. However, a mutation which places Y1062 of Ret51 in a Ret9 context improves only marginally the ability of Ret51 to support renal and enteric nervous system development. Finally, monoisoformic mice expressing a variant of Ret9 in which a C-terminal PDZ-binding motif was mutated develop normally and are healthy. Our studies identify Y1062 as a critical regulator of Ret9 signaling and suggest that Ret51-specific motifs are likely to inhibit the activity of this isoform.

* Corresponding author. Mailing address for Vassilis Pachnis: Division of Molecular Neurobiology, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, United Kingdom. Phone: 44 20 8816 2113. Fax: 44 20 8906 4477. E-mail: vpachni{at}nimr.mrc.ac.uk. Mailing address for Frank Costantini: Department of Genetics and Development, Columbia University Medical Center, 701 W. 168th Street, New York, NY 10032. E-mail: fdc3{at}columbia.edu.

{dagger} These authors have contributed equally to this work.

These authors have contributed equally to this work.

{ddagger} Present address: National Institute of Chemical Physics and Biophysics & Tallinn University of Technology, Department of Gene Technology, Tallinn, Estonia.

§ Present address: Department of Clinical Genetics, Erasmus University, 3015 GE Rotterdam, The Netherlands.

Molecular and Cellular Biology, November 2005, p. 9661-9673, Vol. 25, No. 21
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.21.9661-9673.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Dressler, G. R. (2009). Advances in early kidney specification, development and patterning. Development 136: 3863-3874 [Abstract] [Full Text]  
  • Rozen, E. J., Schmidt, H., Dolcet, X., Basson, M. A., Jain, S., Encinas, M. (2009). Loss of Sprouty1 Rescues Renal Agenesis Caused by Ret Mutation. J. Am. Soc. Nephrol. 20: 255-259 [Abstract] [Full Text]  
  • Horowitz, A., Simons, M. (2008). Branching Morphogenesis. Circ. Res. 103: 784-795 [Abstract] [Full Text]  
  • Bogni, S., Trainor, P., Natarajan, D., Krumlauf, R., Pachnis, V. (2008). Non-cell-autonomous effects of Ret deletion in early enteric neurogenesis. Development 135: 3007-3011 [Abstract] [Full Text]  
  • Boulay, A., Breuleux, M., Stephan, C., Fux, C., Brisken, C., Fiche, M., Wartmann, M., Stumm, M., Lane, H. A., Hynes, N. E. (2008). The Ret Receptor Tyrosine Kinase Pathway Functionally Interacts with the ER{alpha} Pathway in Breast Cancer. Cancer Res. 68: 3743-3751 [Abstract] [Full Text]  
  • Asai, N., Fukuda, T., Wu, Z., Enomoto, A., Pachnis, V., Takahashi, M., Costantini, F. (2006). Targeted mutation of serine 697 in the Ret tyrosine kinase causes migration defect of enteric neural crest cells. Development 133: 4507-4516 [Abstract] [Full Text]  
  • Heanue, T. A., Pachnis, V. (2006). From the Cover: Expression profiling the developing mammalian enteric nervous system identifies marker and candidate Hirschsprung disease genes. Proc. Natl. Acad. Sci. USA 103: 6919-6924 [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»