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JAK2V617F activates Lu/BCAM-mediated red cell adhesion in polycythemia vera through an EpoR-independent Rap1/Akt pathway
- Source :
- Blood, Blood, American Society of Hematology, 2013, 121 (4), pp.658-65. ⟨10.1182/blood-2012-07-440487⟩
- Publication Year :
- 2013
- Publisher :
- American Society of Hematology, 2013.
-
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.
- 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
Subjects
Details
- ISSN :
- 15280020 and 00064971
- Volume :
- 121
- Database :
- OpenAIRE
- Journal :
- Blood
- Accession number :
- edsair.doi.dedup.....fb8f6ae07c509ef94e6c3f764c736e51