JAK2-V617F promotes venous thrombosis through β1/β2 integrin activation
| Autor: | Tina M Schnoeder, Juliane Mohr, Holger Amthauer, Subbaiah Chary Nimmagadda, Soenke Weinert, Anja M. Oelschlegel, Andreas Müller, Burkhart Schraven, Rüdiger C. Braun-Dullaeus, Florian H. Heidel, Jürgen Goldschmidt, Felix C Saalfeld, Peter Müller, Denise Wolleschak, Thomas Fischer, Nibedita Gupta, Aniket Ghosh, Lars Philipsen, Khurrum Shahzad, Berend Isermann, Bärbel Edelmann, Stefanie Kliche |
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| Přispěvatelé: | HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Integrins biology Chemistry Cell adhesion molecule Integrin Spleen Thrombosis General Medicine Hematology Intercellular adhesion molecule Cell biology Cell membrane 03 medical and health sciences 030104 developmental biology 0302 clinical medicine medicine.anatomical_structure 030220 oncology & carcinogenesis hemic and lymphatic diseases biology.protein medicine Rap1 Platelet Antibody |
| Zdroj: | The Journal of clinical investigation The journal of clinical investigation, 128(10):4359-4371 |
| Popis: | JAK2-V617F–positive chronic myeloproliferative neoplasia (CMN) commonly displays dysfunction of integrins and adhesion molecules expressed on platelets, erythrocytes, and leukocytes. However, the mechanism by which the 2 major leukocyte integrin chains, β1 and β2, may contribute to CMN pathophysiology remained unclear. β1 (α4β1; VLA-4) and β2 (αLβ2; LFA-1) integrins are essential regulators for attachment of leukocytes to endothelial cells. We here showed enhanced adhesion of granulocytes from mice with JAK2-V617F knockin (JAK2+/VF mice) to vascular cell adhesion molecule 1– (VCAM1-) and intercellular adhesion molecule 1–coated (ICAM1-coated) surfaces. Soluble VCAM1 and ICAM1 ligand binding assays revealed increased affinity of β1 and β2 integrins for their respective ligands. For β1 integrins, this correlated with a structural change from the low- to the high-affinity conformation induced by JAK2-V617F. JAK2-V617F triggered constitutive activation of the integrin inside-out signaling molecule Rap1, resulting in translocation toward the cell membrane. Employing a venous thrombosis model, we demonstrated that neutralizing anti–VLA-4 and anti–β2 integrin antibodies suppress pathologic thrombosis as observed in JAK2+/VF mice. In addition, aberrant homing of JAK2+/VF leukocytes to the spleen was inhibited by neutralizing anti-β2 antibodies and by pharmacologic inhibition of Rap1. Thus, our findings identified cross-talk between JAK2-V617F and integrin activation promoting pathologic thrombosis and abnormal trafficking of leukocytes to the spleen. |
| Databáze: | OpenAIRE |
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