title: Erythrocyte plasma membrane-bound ERK1/2 activation promotes ICAM-4-mediated sickle red cell adhesion to endothelium.
abstract: 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. β(2)-adrenergic receptor stimulation by epinephrine can enhance ERK1/2 activity only in SS RBCs via PKA- and tyrosine kinase p72(syk)-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.
authors.affiliation: Division of Hematology and Duke Comprehensive Sickle Cell Center, Duke University Medical Center, Durham, NC 27710, USA. zenna001@mc.duke.edu
authors.forename: Rahima
authors.initials: R
authors.lastname: Zennadi
authors.forename: Erin J
authors.initials: EJ
authors.lastname: Whalen
authors.forename: Erik J
authors.initials: EJ
authors.lastname: Soderblom
authors.forename: Susan C
authors.initials: SC
authors.lastname: Alexander
authors.forename: J Will
authors.initials: JW
authors.lastname: Thompson
authors.forename: Laura G
authors.initials: LG
authors.lastname: Dubois
authors.forename: M Arthur
authors.initials: MA
authors.lastname: Moseley
authors.forename: Marilyn J
authors.initials: MJ
authors.lastname: Telen
mesh_terms: D016475:3T3 Cells; D000755:Anemia, Sickle Cell / Q000097:blood* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000378:metabolism / Q000502:physiology*; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000378:metabolism / Q000502:physiology*; D004789:Enzyme Activation / Q000502:physiology; D004910:Erythrocyte Membrane / Q000378:metabolism*; D004913:Erythrocytes, Abnormal / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism / Q000502:physiology; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism / Q000502:physiology; D008954:Models, Biological; D061251:Primary Cell Culture
chemical_list: D015815:Cell Adhesion Molecules; C095100:ICAM4 protein, human; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3