title: Deletion mutant of FGFR4 induces onion-like membrane structures in the nucleus.
abstract: The expression of several deletion mutants of fibroblast growth factor receptor 4 (FGFR4) was studied in COS-1 cells. FGFR4-mutants lacking most of the extracellular region did not efficiently reach the plasma membrane but accumulated in the endoplasmic reticulum (ER) and Golgi body. A mutant FGFR4 lacking the kinase domain as well as most of the extracellular region (DeltaExt/R4Tth) had a distinct intracellular distribution. It localized in part to the nucleus, where it exhibited a striking spotted pattern. Ultrastructural studies showed that the nuclear spots consisted of several layers of membrane that were folded into onion-like structures at the nucleoplasmic side of the nuclear envelope. These intranuclear structures did not contain nuclear pores but were positive for the ER proteins calreticulin and protein disulfide isomerase, in addition to abundant DeltaExt/R4Tth. Formation of the intranuclear structures was sensitive to inhibition of protein kinase C. Live microscopy of a green-fluorescent-protein/DeltaExt/R4Tth fusion protein showed that the intranuclear structures were stable and immobile, suggesting that they function as deposits of the overexpressed mutant and associated membrane. The DeltaExt/R4Tth protein also induced formation of densely packed membrane stacks in the cytosol and we suggest a model were the intranuclear structures are formed by invagination of ER-derived membrane stacks into the nucleus.
authors.affiliation: Institute for Cancer Research, The Norwegian Radium Hospital, Department of Biochemistry, Montebello, 0310 Oslo, Norway.
authors.forename: Vigdis
authors.initials: V
authors.lastname: Sørensen
authors.forename: Andreas
authors.initials: A
authors.lastname: Brech
authors.forename: Denis
authors.initials: D
authors.lastname: Khnykin
authors.forename: Elona
authors.initials: E
authors.lastname: Kolpakova
authors.forename: Lucia
authors.initials: L
authors.lastname: Citores
authors.forename: Sjur
authors.initials: S
authors.lastname: Olsnes
mesh_terms: D000818:Animals; D019556:COS Cells; D002462:Cell Membrane / Q000378:metabolism / Q000648:ultrastructure; D002467:Cell Nucleus / Q000378:metabolism* / Q000648:ultrastructure*; D007211:Indoles / Q000494:pharmacology; D007425:Intracellular Membranes / Q000378:metabolism* / Q000648:ultrastructure; D007546:Isoquinolines / Q000494:pharmacology; D008301:Maleimides / Q000494:pharmacology; D008856:Microscopy, Fluorescence; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D011494:Protein Kinases / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000235:genetics; D051499:Receptor, Fibroblast Growth Factor, Type 4; D017468:Receptors, Fibroblast Growth Factor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017384:Sequence Deletion / Q000235:genetics*; D019311:Staurosporine / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D007211:Indoles; D007546:Isoquinolines; D008301:Maleimides; D017468:Receptors, Fibroblast Growth Factor; D013449:Sulfonamides; D011494:Protein Kinases; D051499:Receptor, Fibroblast Growth Factor, Type 4; D011493:Protein Kinase C; D019311:Staurosporine; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; C088060:bisindolylmaleimide