Geldanamycin selectively targets the nascent form of ERBB3 for degradation.
Heat shock protein 90 (HSP90) targets a broad spectrum of client proteins with divergent modes of interaction and consequences. The homologous epidermal growth factor receptor (EGFR) and ERBB2 receptors as well as kinase-deficient mutants thereof differ in their requirement for HSP90 in the nascent versus mature state of the receptor. Specific features of the kinase domain have been implicated for the selective association of HSP90 with mature ERBB2. We evaluated the role of HSP90 for the homologous ERBB3 receptor. ERBB3 is naturally kinase deficient, a central mediator in cell survival and stress response and the primary dimerization partner for ERBB2 in signaling. Cellular studies indicate that, similar to EGFR, the geldanamycin (GA) sensitivity of ERBB3 and HSP90 binding resides in the nascent state and is dependent on the presence of the kinase domain of ERBB3. Furthermore, despite its intrinsic lack of kinase activity and in contrast to the reported GA sensitivity of mature and kinase-deficient EGFR, the GA sensitivity of the nascent state of ERBB3 appears to be exclusive. Geldanamycin disrupts the interaction of ERBB3 and HSP90 and inhibits ERBB3 maturation at an early stage of synthesis, prior to export from the ER. Studies with a photo-convertible fusion protein of ERBB3 suggest geldanamycin sensitivity at a later stage in maturation, possibly through the putative role of HSP90 in structural proofreading.
Gerbin
Candice S
CS
Department of Biological Chemistry, University of California Los Angeles, Los Angeles, CA, USA.
Landgraf
Ralf
R
D016227:Benzoquinones; D020126:Brefeldin A / Q000378:metabolism; D045744:Cell Line, Tumor; D003513:Cycloheximide / Q000494:pharmacology*; D066246:ErbB Receptors / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D047029:Lactams, Macrocyclic; D008856:Microscopy, Fluorescence; D016133:Polymerase Chain Reaction; D011485:Protein Binding; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism
D016227:Benzoquinones; D020126:Brefeldin A; D003513:Cycloheximide; D066246:ErbB Receptors; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human; C001277:geldanamycin