HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 281, Issue 40, 29886-29896, October 6, 2006

This Article Full Text Full Text (PDF) All Versions of this Article: 281/40/29886    most recent M600473200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lundgren, T. K. Articles by Ernfors, P. Search for Related Content PubMed PubMed Citation Articles by Lundgren, T. K. Articles by Ernfors, P. Social Bookmarking                      What's this?

Engineering the Recruitment of Phosphotyrosine Binding Domain-containing Adaptor Proteins Reveals Distinct Roles for RET Receptor-mediated Cell Survival^*

T. Kalle Lundgren, Rizaldy P. Scott, Matthew Smith, Tony Pawson, and Patrik Ernfors¹

From the Unit of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, 171 77 Stockholm, Sweden and Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada

The RET receptor tyrosine kinase is important for several different biological functions during development. The recruitment at the phosphorylated Tyr¹⁰⁶² site in RET of a number of different phosphotyrosine binding (PTB) domain-containing adaptor proteins, including Shc and Frs2, plays a dominant role for the multiple different biological functions of the RET receptor during development, including stimulation of cell survival. Here, we demonstrate that a competitive recruitment of Shc as opposed to Frs2 mediates the survival signaling arising from RET activation. Based on results from a peptide array, we have genetically engineered the PTB domain binding site of RET to rewire its recruitment of the PTB proteins Shc and Frs2. An engineered RET that has a competitive interaction with Shc at the expense of Frs2, but not a RET receptor that only recruits Frs2, activates cell survival signaling pathways and is protective from cell death in neuronal SK-N-MC cells. Thus, cell type-specific functions involve a competitive recruitment of different PTB adaptor molecules by RET that activate selective signaling pathways.

Received for publication, January 17, 2006 , and in revised form, June 21, 2006.

^* This work was supported by the Swedish Cancer Society, the Swedish Medical Research Council, the Swedish Foundation for Strategic Research (Center of Excellence in Developmental Biology (CEDB) grant) (to P. E.), and the Karolinska Institute M.D.-Ph.D. program (to T. K. L.). 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 To whom correspondence should be addressed: Unit of Molecular Neurobiology, Dept. of Medical Biochemistry and Biophysics, Karolinska Institute, 171 77 Stockholm, Sweden. Tel.: 468-52487659; Fax: 468-341960; E-mail: Patrik.Ernfors{at}ki.se.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				V. Bryja, D. Gradl, A. Schambony, E. Arenas, and G. Schulte beta-Arrestin is a necessary component of Wnt/beta-catenin signaling in vitro and in vivo PNAS, April 17, 2007; 104(16): 6690 - 6695. [Abstract] [Full Text] [PDF]

				M. J. Smith, W. R. Hardy, J. M. Murphy, N. Jones, and T. Pawson Screening for PTB Domain Binding Partners and Ligand Specificity Using Proteome-Derived NPXY Peptide Arrays Mol. Cell. Biol., November 15, 2006; 26(22): 8461 - 8474. [Abstract] [Full Text] [PDF]