title: Inactivation of protein-phosphatase 2A causing hyperphosphorylation of autoantigenic paraprotein targets in MGUS/MM is due to an exchange of its regulatory subunits.
abstract: Hyperphosphorylated paratarg-7 (pP-7) carrier state is the strongest molecularly defined risk factor for monoclonal gammopathy of undetermined significance (MGUS), multiple myeloma (MM) and Waldenstrom's macroglobulinemia (WM). pP-7 is inherited as autosomal-dominant trait and depending on the ethnic background is found in over one-third of MGUS/MM patients. P-7, which is the antigenic paraprotein target in these patients, is hyperphosphorylated at serine17. P-7 hyperphosphorylation can be induced in wild-type P-7 (wtP-7) carriers by PKCζ and reverted by protein-phosphatase 2A (PP2A). Here we show that dephosphorylation of pP-7 is defective in pP-7 carriers due to inactivation of the PP2A by substitution of the regulatory B55δ subunit with B56γ3. In lymphoblastoid cell lines from pP-7 carriers, transfection of recombinant B55δ or treatment with ceramide led to a partial reconstitution of PP2A activity and dephosphorylation of pP-7 to wtP7. Similar results were observed with other previously reported autoantigenic paraproteins targets. In conclusion, the mechanisms responsible for the defective dephosphorylation and maintaining the hyperphosphorylated state of P-7 and other autoantigenic paraprotein targets have been elucidated, facilitating the identification of the genetic basis underlying this phenomenon which is obviously common in the pathogenesis of MGUS/MM/WM and not restricted to pP-7 cases.
authors.affiliation: José-Carreras-Center for Immuno- and Gene Therapy, Internal Medicine I, Saarland University Medical School, Homburg (Saar), Germany.
authors.forename: Klaus-Dieter
authors.initials: KD
authors.lastname: Preuss
authors.forename: Natalie
authors.initials: N
authors.lastname: Fadle
authors.forename: Evi
authors.initials: E
authors.lastname: Regitz
authors.forename: Gerhard
authors.initials: G
authors.lastname: Held
authors.forename: Michael
authors.initials: M
authors.lastname: Pfreundschuh
mesh_terms: D017209:Apoptosis; D001324:Autoantigens / Q000276:immunology*; D015153:Blotting, Western; D049109:Cell Proliferation; D002478:Cells, Cultured; D019175:DNA Methylation; D004797:Enzyme-Linked Immunosorbent Assay; D006579:Heterozygote; D006801:Humans; D047468:Immunoprecipitation; D007525:Isoelectric Focusing; D008998:Monoclonal Gammopathy of Undetermined Significance / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D009101:Multiple Myeloma / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D010266:Paraproteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D010766:Phosphorylation; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D021122:Protein Subunits; D034741:RNA, Small Interfering / Q000235:genetics; D008258:Waldenstrom Macroglobulinemia / Q000276:immunology / Q000378:metabolism* / Q000473:pathology
chemical_list: D001324:Autoantigens; D010266:Paraproteins; D021122:Protein Subunits; D034741:RNA, Small Interfering; D054648:Protein Phosphatase 2
keywords: B-subunit; autoantigen; multiple myeloma; paraprotein; proteinphosphatase 2A