JCB logo
PeproTech: Free Shipping at www.peprotech.com
  Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents
Published online
doi:10.1083/jcb.200905118
The Journal of Cell Biology, Vol. 187, No. 2, 265-277
The Rockefeller University Press, 0021-9525 $30.00
© Mardakheh et al.
This Article
Right arrow Full Text
Right arrow Full Text (PDF, 3223K)
Right arrow PDF+supp data (4201K)
Right arrow PPT slides of all figures
Right arrow Supplemental Material
Right arrow Alert me when this article is cited
Right arrow View original image data
Right arrow Citation Map
Services
Right arrow Email this article
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new content in the JCB
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via CrossRef
Google Scholar
Right arrow Articles by Mardakheh, F. K.
Right arrow Articles by Heath, J. K.
PubMed
Right arrow PubMed Citation
Right arrow Articles by Mardakheh, F. K.
Right arrow Articles by Heath, J. K.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Facebook   Add to Reddit   Add to Technorati   Add to Twitter  
What's this?

Article

Spred2 interaction with the late endosomal protein NBR1 down-regulates fibroblast growth factor receptor signaling



Faraz K. Mardakheh1, Mona Yekezare2, Laura M. Machesky2, and John K. Heath1

1 Cancer Research UK Growth Factor Group and 2 School of Biosciences, University of Birmingham, Birmingham B15 2TT, England, UK

Correspondence to John K. Heath: j.k.heath{at}bham.ac.uk

The potential for modulation of growth factor signaling by endocytic trafficking of receptors is well recognized, but the underlying mechanisms are poorly understood. We examined the regulation of fibroblast growth factor (FGF) signaling by Sprouty related with EVH1 (Ena/VASP homology 1) domain (Spred), a family of signaling inhibitors with proposed tumor-suppressive functions. The inhibitory activity of Spreds has been linked to their N-terminal EVH1 domain, but the molecular mechanism is unknown. In this study, we identify a novel late endosomal protein that directly binds to the EVH1 domain of Spred2. Neighbor of BRCA1 (NBR1) is a highly conserved multidomain protein that interacts and colocalizes with Spred2 in vivo. Attenuation of FGF signaling by Spred2 is dependent on the interaction with NBR1 and is achieved by redirecting the trafficking of activated receptors to the lysosomal degradation pathway. Our findings suggest a critical function for NBR1 in the regulation of receptor trafficking and provide a mechanism for down-regulation of signaling by Spred2 via NBR1.

Abbreviations used in this paper: BafA, bafilomycin A1; ERK, extracellular signal-regulated kinase; EVH1, Ena/VASP homology 1; FGFR, FGF receptor; IB, immunoblot; IP, immunoprecipitation; KBD, Kit-binding domain; MPR, mannose 6-phosphate receptor; NBR1, neighbor of BRCA1; RTK, receptor Tyr kinase; Spred, Sprouty related with EVH1 domain; Tet, tetracycline; TR, Tet-repressor; UBA, ubiquitin associated; WCL, whole cell lysate; WT, wild type.

© 2009 Mardakheh et al.
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jcb.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).


Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Facebook Facebook   Add to Reddit Reddit   Add to Technorati Technorati   Add to Twitter Twitter    What's this?




  Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents