title: The leucine-rich repeat protein LRIG1 is a negative regulator of ErbB family receptor tyrosine kinases.
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 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.
authors.affiliation: University of California Davis Cancer Center, Sacramento, California 95817, USA.
authors.forename: Melanie B
authors.initials: MB
authors.lastname: Laederich
authors.forename: Melanie
authors.initials: M
authors.lastname: Funes-Duran
authors.forename: Lily
authors.initials: L
authors.lastname: Yen
authors.forename: Ellen
authors.initials: E
authors.lastname: Ingalla
authors.forename: Xiuli
authors.initials: X
authors.lastname: Wu
authors.forename: Kermit L
authors.initials: KL
authors.lastname: Carraway
authors.forename: Colleen
authors.initials: C
authors.lastname: Sweeney
mesh_terms: D000362:Agar / Q000737:chemistry; D000818:Animals; D019921:Biotinylation; D019556:COS Cells; D002453:Cell Cycle; D002460:Cell Line; D045744:Cell Line, Tumor; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000378:metabolism; D004330:Drosophila; D066246:ErbB Receptors / Q000737:chemistry*; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D007930:Leucine / Q000737:chemistry*; D008024:Ligands; D008562:Membrane Glycoproteins / Q000737:chemistry*; D051379:Mice; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000737:chemistry*; D020893:Receptor, ErbB-3 / Q000737:chemistry*; D066247:Receptor, ErbB-4; D013997:Time Factors; D014162:Transfection; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D000362:Agar; D018076:DNA, Complementary; D066246:ErbB Receptors; D007930:Leucine; D008024:Ligands; D008562:Membrane Glycoproteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D066247:Receptor, ErbB-4; D025801:Ubiquitin; C484445:LRIG1 protein, human; C587689:ERBB4 protein, human; C587690:Erbb4 protein, mouse