The leucine-rich repeat protein LRIG1 is a negative regulator of ErbB family receptor tyrosine kinases.
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.
Laederich
Melanie B
MB
University of California Davis Cancer Center, Sacramento, California 95817, USA.
Funes-Duran
Melanie
M
Yen
Lily
L
Ingalla
Ellen
E
Wu
Xiuli
X
Carraway
Kermit L
KL
Sweeney
Colleen
C
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
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