title: Quantity control of the ErbB3 receptor tyrosine kinase at the endoplasmic reticulum.
abstract: The ErbB3 receptor tyrosine kinase contributes to a variety of developmental processes, and its overexpression and aberrant activation promote tumor progression and therapeutic resistance. Accumulating evidence suggests that tumor overexpression may be mediated by the loss of posttranscriptional negative regulatory mechanisms, such as protein degradation, that normally keep receptor levels in check. Our previous studies indicate that the RING finger E3 ubiquitin ligase Nrdp1, a protein lost in breast and other tumor types, suppresses ErbB3 levels by mediating ligand-independent receptor ubiquitination and degradation. Here we demonstrate that Nrdp1 preferentially associates with the nascent form of ErbB3 to accelerate its degradation, and we show that the two proteins colocalize at the endoplasmic reticulum (ER). Blocking the exit of ErbB3 from the ER does not affect the ability of Nrdp1 to mediate receptor ubiquitination or degradation, while functional disruption of the conserved ER-associated degradation (ERAD) pathway ATPase VCP/p97 leads to the Nrdp1-dependent accumulation of ubiquitinated ErbB3 but blocks receptor degradation. Further evidence indicates that the ErbB3 targeted by Nrdp1 for degradation is properly folded and fully functional. Collectively, these observations point to a novel mechanism of receptor tyrosine kinase quantity control wherein steady-state levels of signaling-competent receptor are dictated by an ER-localized degradation pathway.
authors.affiliation: Department of Biochemistry and Molecular Medicine and UC Davis Cancer Center, Sacramento, California 95817, USA.
authors.forename: William H D
authors.initials: WH
authors.lastname: Fry
authors.forename: Catalina
authors.initials: C
authors.lastname: Simion
authors.forename: Colleen
authors.initials: C
authors.lastname: Sweeney
authors.forename: Kermit L
authors.initials: KL
authors.lastname: Carraway
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D020126:Brefeldin A / Q000494:pharmacology; D019556:COS Cells; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002522:Chlorocebus aethiops; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D020893:Receptor, ErbB-3 / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D000074405:Valosin Containing Protein
chemical_list: D018797:Cell Cycle Proteins; D011500:Protein Synthesis Inhibitors; D020126:Brefeldin A; C452580:RNF41 protein, human; D044767:Ubiquitin-Protein Ligases; D020893:Receptor, ErbB-3; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein