1. JAK2V617F activates Lu/BCAM-mediated red cell adhesion in polycythemia vera through an EpoR-independent Rap1/Akt pathway
- Author
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Marie-Paule Wautier, Wassim El Nemer, Marie Cambot, Bruno Cassinat, Maria De Grandis, Jean-Luc Wautier, Christine Chomienne, Yves Colin, Caroline Le Van Kim, Protéines de la membrane érythrocytaire et homologues non-érythroides, Université des Antilles et de la Guyane (UAG)-Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), GR-Ex, Laboratoire d'Excellence, Institut National de la Transfusion Sanguine [Paris] (INTS), Unite de Biologie Cellulaire, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hématologie -Immunologie -Cibles thérapeutiques, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), and The work was funded by the Institut National de la Santé et de la Recherche Médicale (Inserm), the Institut National de la Transfusion Sanguine (INTS), and a grant from Région Île-de-France (SESAME 2007 no. F-08-1104/R). The PhD student, Maria De Grandis, was funded by the Ministère de l'Enseignement Supérieur et de la Recherche at the Ecole Doctorale B3MI.
- Subjects
Male ,MESH: Signal Transduction ,Erythrocytes ,MESH: rap1 GTP-Binding Proteins ,MESH: Polycythemia Vera ,Biochemistry ,MESH: Janus Kinase 2 ,Mice ,MESH: Aged, 80 and over ,0302 clinical medicine ,Receptors, Erythropoietin ,MESH: Animals ,Phosphorylation ,Polycythemia Vera ,Aged, 80 and over ,MESH: Aged ,0303 health sciences ,MESH: Middle Aged ,Janus kinase 2 ,biology ,Cell adhesion molecule ,MESH: Erythrocytes ,rap1 GTP-Binding Proteins ,MESH: Laminin ,Hematology ,Middle Aged ,Lutheran Blood-Group System ,MESH: Lutheran Blood-Group System ,030220 oncology & carcinogenesis ,MESH: Cell Adhesion Molecules ,Female ,Signal Transduction ,Immunology ,[SDV.BC]Life Sciences [q-bio]/Cellular Biology ,Cell Line ,MESH: Cell Adhesion ,03 medical and health sciences ,BCAM ,Cell Adhesion ,Animals ,Humans ,MESH: Receptors, Erythropoietin ,Cell adhesion ,MESH: Mice ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Aged ,030304 developmental biology ,MESH: Humans ,MESH: Phosphorylation ,MESH: Proto-Oncogene Proteins c-akt ,Akt/PKB signaling pathway ,Cell Biology ,Janus Kinase 2 ,Molecular biology ,MESH: Male ,MESH: Cell Line ,Erythropoietin receptor ,biology.protein ,Laminin ,Cell Adhesion Molecules ,Proto-Oncogene Proteins c-akt ,MESH: Female - Abstract
Polycythemia vera (PV) is characterized by an increased RBC mass, spontaneous erythroid colony formation, and the JAK2V617F mutation. PV is associated with a high risk of mesenteric and cerebral thrombosis. PV RBC adhesion to endothelial laminin is increased and mediated by phosphorylated erythroid Lu/BCAM. In the present work, we investigated the mechanism responsible for Lu/BCAM phosphorylation in the presence of JAK2V617F using HEL and BaF3 cell lines as well as RBCs from patients with PV. High levels of Rap1-GTP were found in HEL and BaF3 cells expressing JAK2V617F compared with BaF3 cells with wild-type JAK2. This finding was associated with increased Akt activity, Lu/BCAM phosphorylation, and cell adhesion to laminin that were inhibited by the dominant-negative Rap1S17N or by the specific Rap1 inhibitor GGTI-298. Surprisingly, knocking-down EpoR in HEL cells did not alter Akt activity or cell adhesion to laminin. Our findings reveal a novel EpoR-independent Rap1/Akt signaling pathway that is activated by JAK2V617F in circulating PV RBCs and responsible for Lu/BCAM activation. This new characteristic of JAK2V617F could play a critical role in initiating abnormal interactions among circulating and endothelial cells in patients with PV.
- Published
- 2013