title: JAK2V617F activates Lu/BCAM-mediated red cell adhesion in polycythemia vera through an EpoR-independent Rap1/Akt pathway.
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.
authors.affiliation: Inserm U665, Paris, France.
authors.forename: Maria
authors.initials: M
authors.lastname: De Grandis
authors.forename: Marie
authors.initials: M
authors.lastname: Cambot
authors.forename: Marie-Paule
authors.initials: MP
authors.lastname: Wautier
authors.forename: Bruno
authors.initials: B
authors.lastname: Cassinat
authors.forename: Christine
authors.initials: C
authors.lastname: Chomienne
authors.forename: Yves
authors.initials: Y
authors.lastname: Colin
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Wautier
authors.forename: Caroline
authors.initials: C
authors.lastname: Le Van Kim
authors.forename: Wassim
authors.initials: W
authors.lastname: El Nemer
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002448:Cell Adhesion / Q000235:genetics; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004912:Erythrocytes / Q000378:metabolism*; D005260:Female; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics / Q000378:metabolism*; D007797:Laminin / Q000378:metabolism; D008188:Lutheran Blood-Group System / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008875:Middle Aged; D010766:Phosphorylation; D011087:Polycythemia Vera / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017467:Receptors, Erythropoietin / Q000378:metabolism*; D015398:Signal Transduction; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism*
chemical_list: C090228:BCAM protein, human; D015815:Cell Adhesion Molecules; D007797:Laminin; D008188:Lutheran Blood-Group System; D017467:Receptors, Erythropoietin; D053614:Janus Kinase 2; D051057:Proto-Oncogene Proteins c-akt; D020827:rap1 GTP-Binding Proteins