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, Colleen A Sweeney

Research output: Contribution to journalArticle

156 Citations (Scopus)

Abstract

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 203T cells, LBIG1 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 thai 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.

Original languageEnglish (US)
Pages (from-to)47050-47056
Number of pages7
JournalJournal of Biological Chemistry
Volume279
Issue number45
DOIs
StatePublished - Nov 5 2004

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Receptor Protein-Tyrosine Kinases
Epidermal Growth Factor Receptor
Protein-Tyrosine Kinases
Ubiquitination
Epidermal Growth Factor
Cells
Neuregulin-1
Fibroblasts
Drosophila melanogaster
Leucine
Half-Life
Immunoglobulins
Tumors
Prostate
Molecular Biology
Intercellular Signaling Peptides and Proteins
Cell Cycle
Proteins
Ligands
Feedback

ASJC Scopus subject areas

  • Biochemistry

Cite this

The leucine-rich repeat protein LRIG1 is a negative regulator of ErbB family receptor tyrosine kinases. / Laederich, Melanie B.; Funes-Duran, Melanie; Yen, Lily; Ingalla, Ellen; Wu, Xiuli; Carraway, Kermit L; Sweeney, Colleen A.

In: Journal of Biological Chemistry, Vol. 279, No. 45, 05.11.2004, p. 47050-47056.

Research output: Contribution to journalArticle

Laederich, Melanie B. ; Funes-Duran, Melanie ; Yen, Lily ; Ingalla, Ellen ; Wu, Xiuli ; Carraway, Kermit L ; Sweeney, Colleen A. / The leucine-rich repeat protein LRIG1 is a negative regulator of ErbB family receptor tyrosine kinases. In: Journal of Biological Chemistry. 2004 ; Vol. 279, No. 45. pp. 47050-47056.
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