Erythrocyte plasma membrane–bound ERK1/2 activation promotes ICAM-4–mediated sickle red cell adhesion to endothelium

• Published in: Blood Vol. 119; no. 5; pp. 1217 - 1227
• Main Authors: Zennadi, Rahima, Whalen, Erin J., Soderblom, Erik J., Alexander, Susan C., Thompson, J. Will, Dubois, Laura G., Moseley, M. Arthur, Telen, Marilyn J.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 02-02-2012; Americain Society of Hematology; American Society of Hematology
• Subjects: 3T3 Cells; Anemia, Sickle Cell - blood; Anemia, Sickle Cell - metabolism; Anemia, Sickle Cell - pathology; Anemias. Hemoglobinopathies; Animals; Biological and medical sciences; Cell Adhesion; Cell Adhesion Molecules - metabolism; Cell Adhesion Molecules - physiology; Cell Membrane - metabolism; Cells, Cultured; Diseases of red blood cells; Endothelium, Vascular - metabolism; Endothelium, Vascular - physiology; Enzyme Activation - physiology; Erythrocyte Membrane - metabolism; Erythrocytes, Abnormal - metabolism; Erythrocytes, Abnormal - pathology; Erythrocytes, Abnormal - physiology; Hematologic and hematopoietic diseases; Human Umbilical Vein Endothelial Cells - metabolism; Human Umbilical Vein Endothelial Cells - pathology; Human Umbilical Vein Endothelial Cells - physiology; Humans; MAP Kinase Signaling System - physiology; Medical sciences; Mice; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 1 - physiology; Mitogen-Activated Protein Kinase 3 - metabolism; Mitogen-Activated Protein Kinase 3 - physiology; Models, Biological; Primary Cell Culture; Red Cells, Iron, and Erythropoiesis; Hemoglobinopathy; Sickle cell anemia; Hematology; Intercellular adhesion molecule 2; Cell adhesion molecule; Red blood cell; Hemopathy; Adhesion; Genetic disease; Endothelium; Blood cell; Extracellular signal-regulated protein kinase 2; Hemolytic anemia; Extracellular signal-regulated protein kinase 1; Plasma membrane
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2011-03-344440

The core pathology of sickle cell disease (SCD) starts with the erythrocyte (RBC). Aberration in MAPK/ERK1/2 signaling, which can regulate cell adhesion, occurs in diverse pathologies. Because RBCs contain abundant ERK1/2, we predicted that ERK1/2 is functional in sickle (SS) RBCs and promotes adherence, a hallmark of SCD. ERK1/2 remained active in SS but not normal RBCs. β2-adrenergic receptor stimulation by epinephrine can enhance ERK1/2 activity only in SS RBCs via PKA- and tyrosine kinase p72syk-dependent pathways. ERK signaling is implicated in RBC ICAM-4 phosphorylation, promoting SS RBC adhesion to the endothelium. SS RBC adhesion and phosphorylation of both ERK and ICAM-4 all decreased with continued cell exposure to epinephrine, implying that activation of ICAM-4–mediated SS RBC adhesion is temporally associated with ERK1/2 activation. Furthermore, recombinant ERK2 phosphorylated α- and β-adducins and dematin at the ERK consensus motif. Cytoskeletal protein 4.1 also showed dynamic phosphorylation but not at the ERK consensus motif. These results demonstrate that ERK activation induces phosphorylation of cytoskeletal proteins and the adhesion molecule ICAM-4, promoting SS RBC adhesion to the endothelium. Thus, blocking RBC ERK1/2 activation, such as that promoted by catecholamine stress hormones, could ameliorate SCD pathophysiology.