title: Calreticulin and Hsp90 stabilize the human insulin receptor and promote its mobility in the endoplasmic reticulum.
abstract: Elimination of misfolded membrane proteins in the endoplasmic reticulum (ER) affects cell survival and growth and can be triggered by either local physiologic events or disease-associated mutations. Regulation of signaling receptor degradation involves both cytosolic and ER luminal molecular chaperones, but the mechanisms and timing of this process remain uncertain. Here we report that calreticulin (CRT) and Hsp90 exert distinct effects on the stability and cell surface levels of native and misfolded forms of the human insulin receptor (hIR) and a human variant found in type A insulin resistance. CRT was unique in stabilizing the disease variant and in augmenting hIR expression when glycolysis was abrogated. Effects of Hsp90 were independent of receptor tyrosine phosphorylation and did not change levels of downstream signaling kinases. Live cell imaging revealed that movement of the hIR through the ER was accelerated by misfolding or by overexpression of either CRT or Hsp90. Together, our results indicate that both CRT and Hsp90 control expression of hIR at its earliest maturation stages and modulate its movement within the ER before either degradation or cell surface expression.
authors.affiliation: Department of Medicine, Northwestern University, Evanston, IL 60208, USA.
authors.forename: Rowena R
authors.initials: RR
authors.lastname: Ramos
authors.forename: Andrea J
authors.initials: AJ
authors.lastname: Swanson
authors.forename: Joseph
authors.initials: J
authors.lastname: Bass
mesh_terms: D015703:Antigens, CD / Q000378:metabolism*; D000963:Antimetabolites / Q000494:pharmacology; D037282:Calreticulin / Q000378:metabolism*; D002460:Cell Line; D003847:Deoxyglucose / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D049452:Green Fluorescent Proteins / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007212:Indolizines / Q000494:pharmacology; D007333:Insulin Resistance; D018832:Molecular Chaperones / Q000378:metabolism*; D020125:Mutation, Missense; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D011972:Receptor, Insulin / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013997:Time Factors; D054836:Indolizidines
chemical_list: D015703:Antigens, CD; D000963:Antimetabolites; D037282:Calreticulin; D003847:Deoxyglucose; D004791:Enzyme Inhibitors; D049452:Green Fluorescent Proteins; D018841:HSP90 Heat-Shock Proteins; D007212:Indolizines; D018832:Molecular Chaperones; D046988:Proteasome Endopeptidase Complex; D011972:Receptor, Insulin; D011993:Recombinant Fusion Proteins; C435941:INSR protein, human; C037806:castanospermine; D054836:Indolizidines