TY - JOUR
T1 - Inhibition of Band 3 tyrosine phosphorylation
T2 - a new mechanism for treatment of sickle cell disease
AU - Noomuna, Panae
AU - Risinger, Mary
AU - Zhou, Sitong
AU - Seu, Katie
AU - Man, Yuncheng
AU - An, Ran
AU - Sheik, Daniel A.
AU - Wan, Jiandi
AU - Little, Jane A.
AU - Gurkan, Umut A.
AU - Turrini, Francesco M.
AU - Kalfa, Theodosia
AU - Low, Philip S.
N1 - Funding Information:
This work was supported by NIH grants R01GM24417‐40 (P.S.L.), 1RF1 NS110049‐01 (J.W.), R01HL133574 (U.A.G. and J.A.L.), T32HL134622 (R.A.), and NSF #1552782 (U.A.G.). We thank Suzie A. Noronha for providing sickle cell samples from URMC. We thank Ruhani Sansoya for her assistance with the lab‐related work.
Funding Information:
This work was supported by NIH grants R01GM24417-40 (P.S.L.), 1RF1 NS110049-01 (J.W.), R01HL133574 (U.A.G. and J.A.L.), T32HL134622 (R.A.), and NSF #1552782 (U.A.G.). We thank Suzie A. Noronha for providing sickle cell samples from URMC. We thank Ruhani Sansoya for her assistance with the lab-related work.
Publisher Copyright:
© 2020 British Society for Haematology and John Wiley & Sons Ltd
PY - 2020/8/1
Y1 - 2020/8/1
N2 - Many hypotheses have been proposed to explain how a glutamate to valine substitution in sickle haemoglobin (HbS) can cause sickle cell disease (SCD). We propose and document a new mechanism in which elevated tyrosine phosphorylation of Band 3 initiates sequelae that cause vaso-occlusion and the symptoms of SCD. In this mechanism, denaturation of HbS and release of heme generate intracellular oxidants which cause inhibition of erythrocyte tyrosine phosphatases, thus permitting constitutive tyrosine phosphorylation of Band 3. This phosphorylation in turn induces dissociation of the spectrin-actin cytoskeleton from the membrane, leading to membrane weakening, discharge of membrane-derived microparticles (which initiate the coagulation cascade) and release of cell-free HbS (which consumes nitric oxide) and activates the endothelium to express adhesion receptors). These processes promote vaso-occlusive events which cause SCD. We further show that inhibitors of Syk tyrosine kinase block Band 3 tyrosine phosphorylation, prevent release of cell-free Hb, inhibit discharge of membrane-derived microparticles, increase sickle cell deformability, reduce sickle cell adhesion to human endothelial cells, and enhance sickle cell flow through microcapillaries. In view of reports that imatinib (a Syk inhibitor) successfully treats symptoms of sickle cell disease, we suggest that Syk tyrosine kinase inhibitors warrant repurposing as potential treatments for SCD.
AB - Many hypotheses have been proposed to explain how a glutamate to valine substitution in sickle haemoglobin (HbS) can cause sickle cell disease (SCD). We propose and document a new mechanism in which elevated tyrosine phosphorylation of Band 3 initiates sequelae that cause vaso-occlusion and the symptoms of SCD. In this mechanism, denaturation of HbS and release of heme generate intracellular oxidants which cause inhibition of erythrocyte tyrosine phosphatases, thus permitting constitutive tyrosine phosphorylation of Band 3. This phosphorylation in turn induces dissociation of the spectrin-actin cytoskeleton from the membrane, leading to membrane weakening, discharge of membrane-derived microparticles (which initiate the coagulation cascade) and release of cell-free HbS (which consumes nitric oxide) and activates the endothelium to express adhesion receptors). These processes promote vaso-occlusive events which cause SCD. We further show that inhibitors of Syk tyrosine kinase block Band 3 tyrosine phosphorylation, prevent release of cell-free Hb, inhibit discharge of membrane-derived microparticles, increase sickle cell deformability, reduce sickle cell adhesion to human endothelial cells, and enhance sickle cell flow through microcapillaries. In view of reports that imatinib (a Syk inhibitor) successfully treats symptoms of sickle cell disease, we suggest that Syk tyrosine kinase inhibitors warrant repurposing as potential treatments for SCD.
KW - anion exchanger 1
KW - erythrocyte membrane
KW - haemoglobinopathy
KW - sickle cell disease
KW - tyrosine phosphorylation
KW - Plasma
KW - Oxidative Stress
KW - beta-Thalassemia/blood
KW - Humans
KW - Phosphotyrosine/metabolism
KW - Drug Evaluation, Preclinical
KW - Endothelium, Vascular/metabolism
KW - Anemia, Sickle Cell/blood
KW - Cell Adhesion/drug effects
KW - Imatinib Mesylate/pharmacology
KW - Erythrocytes, Abnormal/drug effects
KW - Hemoglobin, Sickle/analysis
KW - Sickle Cell Trait/blood
KW - Erythrocyte Deformability/drug effects
KW - Anion Exchange Protein 1, Erythrocyte/metabolism
KW - Protein Processing, Post-Translational/drug effects
KW - Protein Kinase Inhibitors/pharmacology
KW - Cell-Derived Microparticles/chemistry
KW - Erythrocyte Membrane/drug effects
KW - Oxygen/blood
KW - Phosphorylation/drug effects
UR - http://www.scopus.com/inward/record.url?scp=85083984501&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85083984501&partnerID=8YFLogxK
U2 - 10.1111/bjh.16671
DO - 10.1111/bjh.16671
M3 - Article
C2 - 32346864
AN - SCOPUS:85083984501
SN - 0007-1048
VL - 190
SP - 599
EP - 609
JO - British Journal of Haematology
JF - British Journal of Haematology
IS - 4
ER -