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A soluble ectodomain of LRIG1 inhibits cancer cell growth by attenuating basal and ligand-dependent EGFR activity

Oncogene volume 26, pages 368–381 (2007)Cite this article

Abstract

Leucine-rich repeats and immunoglobulin-like domains-1 (LRIG1) is a transmembrane protein with an ectodomain containing 15 leucine-rich repeats (LRRs) homologous to mammalian decorin and the Drosophila kekkon1 gene. In this study, we demonstrate that a soluble ectodomain of LRIG1, containing only the LRRs, inhibits ligand-independent epidermal growth factor receptor (EGFR) activation and causes growth inhibition of A431, HeLa and MDA-468 carcinoma cells. In contrast, cells that do not express detectable levels of EGFR fail to respond to soluble LRIG1. However, when a functional EGFR gene is introduced in these cells, they become growth-inhibited by soluble LRIG1 protein. Furthermore, we demonstrate the existence of high-affinity (Kd=10 nM) binding sites on the A431 cells that can be competitively displaced (up to 75%) by molar excess of EGF. Even more powerful effects are obtained with a chimeric proteoglycan harboring the N-terminus of decorin, substituted with a single glycosaminoglycan chain, fused to the LRIG1 ectodomain. Both proteins also inhibit ligand-dependent activation of the EGFR and extracellular signal-regulated protein kinase 1/2 signaling in a rapid and dose-dependent manner. These results suggest a novel mechanism of action evoked by a soluble ectodomain of LRIG1 protein that could modulate EGFR signaling and its growth-promoting activity. Attenuation of EGFR activity without physical downregulation of the receptor could represent a novel therapeutic approach toward malignancies in which EGFR plays a primary role in tumor growth and survival.

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Abbreviations

EGFR:

epidermal growth factor receptor

LRIG1:

leucine-rich repeats and immunoglobulin-like domains-1

LRIG1ecto:

a soluble form of LRIG1 containing only the extracellular leucine-rich domain

Dcn-LRIG1ecto:

a chimeric proteoglycan harboring the N-terminus of decorin fused to LRIG1ecto

CFP:

cyan fluorescent protein

SDS–PAGE:

sodium dodecylsulfate–polyacrylamide gel electrophoresis

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Acknowledgements

We thank Alexander Sorkin for generously providing the EGFR-CFP construct, Kevin J Williams for the use of the γ-counter, Maurizio Mongiat for supplying the pCEP-Pu vector and Ulrich Rodeck for providing Iressa and valuable suggestions. This work was supported in part by National Institutes of Health Grants RO1 CA39481 and RO1 CA47282, and Department of the Army Grants DAMD17-00-1-0425 (to RVI).

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Authors and Affiliations

  1. Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA

    S Goldoni, R A Iozzo, P Kay, S Campbell, A McQuillan, C Agnew, J-X Zhu, C C Reed & R V Iozzo

  2. The Shriners Hospital for Children, Portland, OR, USA

    D R Keene

  3. The Cellular Biology and Signaling Program, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA

    R V Iozzo

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  1. S Goldoni
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  2. R A Iozzo
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Correspondence to R V Iozzo.

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Goldoni, S., Iozzo, R., Kay, P. et al. A soluble ectodomain of LRIG1 inhibits cancer cell growth by attenuating basal and ligand-dependent EGFR activity. Oncogene 26, 368–381 (2007). https://doi.org/10.1038/sj.onc.1209803

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