title: Erythrocyte membrane changes of chorea-acanthocytosis are the result of altered Lyn kinase activity.
abstract: Acanthocytic RBCs are a peculiar diagnostic feature of chorea-acanthocytosis (ChAc), a rare autosomal recessive neurodegenerative disorder. Although recent years have witnessed some progress in the molecular characterization of ChAc, the mechanism(s) responsible for generation of acanthocytes in ChAc is largely unknown. As the membrane protein composition of ChAc RBCs is similar to that of normal RBCs, we evaluated the tyrosine (Tyr)-phosphorylation profile of RBCs using comparative proteomics. Increased Tyr phosphorylation state of several membrane proteins, including band 3, β-spectrin, and adducin, was noted in ChAc RBCs. In particular, band 3 was highly phosphorylated on the Tyr-904 residue, a functional target of Lyn, but not on Tyr-8, a functional target of Syk. In ChAc RBCs, band 3 Tyr phosphorylation by Lyn was independent of the canonical Syk-mediated pathway. The ChAc-associated alterations in RBC membrane protein organization appear to be the result of increased Tyr phosphorylation leading to altered linkage of band 3 to the junctional complexes involved in anchoring the membrane to the cytoskeleton as supported by coimmunoprecipitation of β-adducin with band 3 only in ChAc RBC-membrane treated with the Lyn-inhibitor PP2. We propose this altered association between membrane skeleton and membrane proteins as novel mechanism in the generation of acanthocytes in ChAc.
authors.affiliation: Department of Medicine, University of Verona, Piazzale Lo Scuro 10, Verona, Italy. lucia.defranceschi@univr.it
authors.forename: Lucia
authors.initials: L
authors.lastname: De Franceschi
authors.forename: Carlo
authors.initials: C
authors.lastname: Tomelleri
authors.forename: Alessandro
authors.initials: A
authors.lastname: Matte
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Brunati
authors.forename: Petra H
authors.initials: PH
authors.lastname: Bovee-Geurts
authors.forename: Mariarita
authors.initials: M
authors.lastname: Bertoldi
authors.forename: Edwin
authors.initials: E
authors.lastname: Lasonder
authors.forename: Elena
authors.initials: E
authors.lastname: Tibaldi
authors.forename: Adrian
authors.initials: A
authors.lastname: Danek
authors.forename: Ruth H
authors.initials: RH
authors.lastname: Walker
authors.forename: Hans H
authors.initials: HH
authors.lastname: Jung
authors.forename: Benedikt
authors.initials: B
authors.lastname: Bader
authors.forename: Angela
authors.initials: A
authors.lastname: Siciliano
authors.forename: Emanuela
authors.initials: E
authors.lastname: Ferru
authors.forename: Narla
authors.initials: N
authors.lastname: Mohandas
authors.forename: Giel J C G M
authors.initials: GJ
authors.lastname: Bosman
mesh_terms: D000050:Acanthocytes / Q000201:enzymology* / Q000473:pathology; D000328:Adult; D001457:Anion Exchange Protein 1, Erythrocyte / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism; D004789:Enzyme Activation / Q000502:physiology; D004910:Erythrocyte Membrane / Q000201:enzymology* / Q000473:pathology; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D054546:Neuroacanthocytosis / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D040901:Proteomics; D000072377:Syk Kinase; D014443:Tyrosine / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism*; D000099291:Adducins
chemical_list: D001457:Anion Exchange Protein 1, Erythrocyte; D003598:Cytoskeletal Proteins; D047908:Intracellular Signaling Peptides and Proteins; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; D014443:Tyrosine; D019061:src-Family Kinases; C501062:ADD2 protein, human; D000099291:Adducins; C000606896:SYK protein, human; C060902:lyn protein-tyrosine kinase