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  • Original Paper
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v-Src induces Shc binding to tyrosine 63 in the cytoplasmic domain of the LDL receptor-related protein 1

Oncogene volume 22, pages 3589–3597 (2003)Cite this article

Abstract

We recently observed that the LDL receptor-related protein 1 (LRP-1) is tyrosine phosphorylated in v-Src-transformed cells. Using a GST-fusion protein containing the cytoplasmic domain of LRP-1, we show that LRP-1 is a direct substrate for v-Src in vitro. To study LRP-1 phosphorylation in vivo, we constructed an LRP-1 minireceptor composed of the β chain linked at the amino-terminus to a Myc epitope (Myc-LRPβ). When expressed together with v-Src, Myc-LRPβ becomes phosphorylated on tyrosine. Of the four tyrosine residues present in the cytoplasmic domain of LRP-1, only Tyr 63 is phosphorylated by v-Src in vivo or in vitro. Using fibroblasts deficient in Src, Yes and Fyn, we were able to show that there are multiple kinases present in the cell that can phosphorylate LRP-1. Tyrosine-phosphorylated LRP-1 associates with Shc, a PTB and SH2 domain containing signaling protein that is involved in the activation of Ras. Binding of the purified Shc PTB domain to Tyr 63 containing peptides shows that the interaction between LRP-1 and Shc is direct. We found that DAB, a PTB domain containing signaling protein that is involved in signaling by LDL receptor-related proteins in the nervous system, did not bind to full-length LRP-1. Our observations suggest that LRP-1 may be involved in normal and malignant signal transduction through a direct interaction with Shc adaptor proteins.

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Acknowledgements

We thank Jeremy Copp and Sandy Wiley for critically reading the manuscript. This work was supported in part by Grant R29 CA78629 from the NIH, HB was supported by NIH training Grant DK 07233.

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Authors and Affiliations

  1. Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Dr, La Jolla, 92093-0601, CA, USA

    Helen Barnes & Peter van der Geer

  2. Neurogenetics Inc., 11085 North Torrey Pines Road, Suite 300, La Jolla, 92037, CA, USA

    Elizabeth J Ackermann

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  1. Helen Barnes
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Correspondence to Peter van der Geer.

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Barnes, H., Ackermann, E. & van der Geer, P. v-Src induces Shc binding to tyrosine 63 in the cytoplasmic domain of the LDL receptor-related protein 1. Oncogene 22, 3589–3597 (2003). https://doi.org/10.1038/sj.onc.1206504

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