Altered phosphorylation of cytoskeleton proteins in sickle red blood cells: the role of protein kinase C, Rac GTPases, and reactive oxygen species.
The small Rho GTPases Rac1 and Rac2 regulate actin structures and mediate reactive oxygen species (ROS) production via NADPH oxidase in a variety of cells. We have demonstrated that deficiency of Rac1 and Rac2 GTPases in mice disrupts the normal hexagonal organization of the RBC cytoskeleton and reduces erythrocyte deformability. This is associated with increased phosphorylation of adducin at Ser-724, (corresponding to Ser-726 in human erythrocytes), a domain target of protein kinase C (PKC). PKC phosphorylates adducin and leads to decreased F-actin capping and dissociation of spectrin from actin, implicating a significant role of such phosphorylation in cytoskeletal remodeling. We evaluated adducin phosphorylation in erythrocytes from patients with sickle cell disease and found it consistently increased at Ser-726. In addition, ROS concentration is elevated in sickle erythrocytes by 150-250% compared to erythrocytes from normal control individuals. Here, we review previous studies demonstrating that altered phosphorylation of erythrocyte cytoskeletal proteins and increased ROS production result in disruption of cytoskeleton stability in healthy and sickle cell erythrocytes. We discuss in particular the known and potential roles of protein kinase C and the Rac GTPases in these two processes.
George
Alex
A
Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, OH, USA.
Pushkaran
Suvarnamala
S
Li
Lina
L
An
Xiuli
X
Zheng
Yi
Y
Mohandas
Narla
N
Joiner
Clinton H
CH
Kalfa
Theodosia A
TA
D000755:Anemia, Sickle Cell / Q000201:enzymology / Q000378:metabolism*; D000818:Animals; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D004912:Erythrocytes / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D011493:Protein Kinase C / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D020744:rac GTP-Binding Proteins / Q000378:metabolism*
D003598:Cytoskeletal Proteins; D017382:Reactive Oxygen Species; D011493:Protein Kinase C; D020744:rac GTP-Binding Proteins