Erythrocyte membrane changes of chorea-acanthocytosis are the result of altered Lyn kinase activity

Department of Medicine, University of Verona, Piazzale Lo Scuro 10, Verona, Italy.
Blood (Impact Factor: 10.45). 09/2011; 118(20):5652-63. DOI: 10.1182/blood-2011-05-355339
Source: PubMed


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.

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    • "Foller et al. [30] found altered signaling of PI3K, Rac1 and PAK1 and a higher fraction of depolymerized actin in ChAc erythrocytes indicating an impaired assembly of the junctional complex. DeFranceschi et al. [31] describe increased tyrosine phosphorylation of the cytoskeletal components β-spectrin and adducin and the integral membrane protein band 3 and implicate alterations in the composition of the junctional complex from co-immunoprecipitation studies. Increased phosphorylation and activity of the band 3 anion exchanger in ChAc erythrocytes has already been reported previously [32]. "
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    • "1SA and 1SB). The combined treatment with Na-vanadate and diamide produced the highest levels of phosphorylation of Tyr 8 on band 3, in agreement with previous reports [28] [20]. As these studies involved exposing intact red cells to oxidative agents it is difficult to discriminate if the observed effects on membrane association of PRDX2 are the result of membrane modifications or modification of PRDX2 or both. "
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