The leucine-rich repeat protein LRIG1 is a negative regulator of ErbB family receptor tyrosine kinases

J Biol Chem. 2004 Nov 5;279(45):47050-6. doi: 10.1074/jbc.M409703200. Epub 2004 Sep 1.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Agar / chemistry
  • Animals
  • Biotinylation
  • COS Cells
  • Cell Cycle
  • Cell Line
  • Cell Line, Tumor
  • Cloning, Molecular
  • DNA, Complementary / metabolism
  • Drosophila
  • ErbB Receptors / chemistry*
  • Fibroblasts / metabolism
  • Humans
  • Immunoprecipitation
  • Leucine / chemistry*
  • Ligands
  • Membrane Glycoproteins / chemistry*
  • Mice
  • Molecular Sequence Data
  • NIH 3T3 Cells
  • Protein Binding
  • Protein Structure, Tertiary
  • Receptor, ErbB-2 / chemistry*
  • Receptor, ErbB-3 / chemistry*
  • Receptor, ErbB-4
  • Time Factors
  • Transfection
  • Ubiquitin / metabolism


  • DNA, Complementary
  • LRIG1 protein, human
  • Ligands
  • Membrane Glycoproteins
  • Ubiquitin
  • Agar
  • ERBB4 protein, human
  • ErbB Receptors
  • Erbb4 protein, mouse
  • Receptor, ErbB-2
  • Receptor, ErbB-3
  • Receptor, ErbB-4
  • Leucine

Associated data

  • GENBANK/AY370707