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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.
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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.
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