title: Leucine-rich repeat and immunoglobulin domain-containing protein-1 (Lrig1) negative regulatory action toward ErbB receptor tyrosine kinases is opposed by leucine-rich repeat and immunoglobulin domain-containing protein 3 (Lrig3).
abstract: Lrig1 is the founding member of the Lrig family of transmembrane leucine-rich repeat proteins, which also includes Lrig2 and Lrig3. Lrig1 is a negative regulator of oncogenic receptor tyrosine kinases, including ErbB and Met receptors, and promotes receptor degradation. Lrig1 has recently emerged as both a tumor suppressor and a key regulator of epidermal and epithelial stem cell quiescence. Despite this, little is known of the mechanisms by which Lrig1 is regulated. Lrig3 was recently reported to increase ErbB receptor expression suggesting that it may function in a manner opposite to Lrig1. In this study, we explore the interaction between Lrig1 and Lrig3 and demonstrate that Lrig1 and Lrig3 functionally oppose one another. Lrig3 opposes Lrig1 negative regulatory activity and stabilizes ErbB receptors. Conversely, Lrig1 destabilizes Lrig3, limiting Lrig3's positive effects on receptors and identifying Lrig3 as a new target of Lrig1. These studies provide new insight into the regulation of Lrig1 and uncover a complex cross-talk between Lrig1 and Lrig3.
authors.affiliation: Department of Biochemistry and Molecular Medicine, University of California at Davis Comprehensive Cancer Center, Sacramento, California 95817, USA.
authors.forename: Hanine
authors.initials: H
authors.lastname: Rafidi
authors.forename: Francisco
authors.initials: F
authors.lastname: Mercado
authors.forename: Michael
authors.initials: M
authors.lastname: Astudillo
authors.forename: William H D
authors.initials: WH
authors.lastname: Fry
authors.forename: Matthew
authors.initials: M
authors.lastname: Saldana
authors.forename: Kermit L
authors.initials: KL
authors.lastname: Carraway
authors.forename: Colleen
authors.initials: C
authors.lastname: Sweeney
mesh_terms: D000818:Animals; D015153:Blotting, Western; D016466:CHO Cells; D045744:Cell Line, Tumor; D006224:Cricetinae; D003412:Cricetulus; D004705:Endocytosis; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D061986:MCF-7 Cells; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D011485:Protein Binding; D055550:Protein Stability; D034622:RNA Interference; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D020893:Receptor, ErbB-3 / Q000235:genetics / Q000378:metabolism*; D066247:Receptor, ErbB-4
chemical_list: D066246:ErbB Receptors; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D066247:Receptor, ErbB-4; C484445:LRIG1 protein, human; C496406:LRIG3 protein, human; C508053:ERBB2 protein, human; C581292:ERBB3 protein, human; C587689:ERBB4 protein, human
keywords: Epidermal Growth Factor Receptor (EGFR); Growth Factor; Lrig1; Lrig3; Protein Degradation; Receptor Tyrosine Kinase; Signal Transduction; Tumor Suppressor Gene