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J. Biol. Chem., Vol. 279, Issue 45, 47050-47056, November 5, 2004

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The Leucine-rich Repeat Protein LRIG1 Is a Negative Regulator of ErbB Family Receptor Tyrosine Kinases^*

Melanie B. Laederich, Melanie Funes-Duran, Lily Yen, Ellen Ingalla, Xiuli Wu, Kermit L. Carraway, III, and Colleen Sweeney¶

From the University of California Davis Cancer Center, Sacramento, California 95817

The molecular mechanisms by which mammalian receptor tyrosine kinases are negatively regulated remain largely unexplored. Previous genetic and biochemical studies indicate that Kekkon-1, a transmembrane protein containing leucine-rich repeats and an immunoglobulin-like domain in its extracellular region, acts as a feedback negative regulator of epidermal growth factor (EGF) receptor signaling in Drosophila melanogaster development. Here we tested whether the related human LRIG1 (also called Lig-1) protein can act as a negative regulator of EGF receptor and its relatives, ErbB2, ErbB3, and ErbB4. We observed that in co-transfected 293T cells, LRIG1 forms a complex with each of the ErbB receptors independent of growth factor binding. We further observed that co-expression of LRIG1 with EGF receptor suppresses cellular receptor levels, shortens receptor half-life, and enhances ligand-stimulated receptor ubiquitination. Finally, we observed that co-expression of LRIG1 suppresses EGF-stimulated transformation of NIH3T3 fibroblasts and that the inducible expression of LRIG1 in PC3 prostate tumor cells suppresses EGF- and neuregulin-1-stimulated cell cycle progression. Our observations indicate that LRIG1 is a negative regulator of the ErbB family of receptor tyrosine kinases and suggest that LRIG1-mediated receptor ubiquitination and degradation may contribute to the suppression of ErbB receptor function.

Received for publication, August 24, 2004 , and in revised form, September 1, 2004.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AY730707.

^* 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.

Recipient of a California Breast Cancer Research Program supplemental award (7KB-0085S).

Recipient of a Department of Defense Breast Cancer Research Program postdoctoral fellowship.

^¶ To whom correspondence should be addressed: UC Davis Cancer Center, Research Bldg. III, Rm. 1400, 4645 2nd Ave., Sacramento, CA 95817. Tel.: 916-734-0726; Fax: 916-734-0190; E-mail: casweeney{at}ucdavis.edu.

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