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: Lucia De Franceschi, Carlo Tomelleri, Alessandro Matte, Anna Maria Brunati, Petra H Bovee-Geurts, Mariarita Bertoldi, Edwin Lasonder, Elena Tibaldi, Adrian Danek, Ruth H Walker, Hans H Jung, Benedikt Bader, Angela Siciliano, Emanuela Ferru, Narla Mohandas, Giel J C G M Bosman
• Journal: Blood (Blood) Vol. 118 Issue 20 Pg. 5652-63 (Nov 17 2011) ISSN: 1528-0020 [Electronic] United States
• PMID: 21951684 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ADD2 protein, human
• Anion Exchange Protein 1, Erythrocyte
• Cytoskeletal Proteins
• Intracellular Signaling Peptides and Proteins
• Tyrosine
• Protein-Tyrosine Kinases
• SYK protein, human
• Syk Kinase
• lyn protein-tyrosine kinase
• src-Family Kinases

Topics

• Acanthocytes (enzymology, pathology)
• Adult
• Anion Exchange Protein 1, Erythrocyte (metabolism)
• Cytoskeletal Proteins (metabolism)
• Cytoskeleton (metabolism)
• Enzyme Activation (physiology)
• Erythrocyte Membrane (enzymology, pathology)
• Female
• Humans
• Intracellular Signaling Peptides and Proteins (metabolism)
• Male
• Middle Aged
• Neuroacanthocytosis (metabolism, pathology)
• Phosphorylation (physiology)
• Protein-Tyrosine Kinases (metabolism)
• Proteomics
• Syk Kinase
• Tyrosine (metabolism)
• src-Family Kinases (metabolism)