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Blood. 2018 Mar 1;131(9):1000-1011. doi: 10.1182/blood-2017-08-800359. Epub 2017 Nov 29.

Nbeal2 interacts with Dock7, Sec16a, and Vac14.

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Department of Haematology, University of Cambridge, Cambridge, United Kingdom.
National Health Service Blood and Transplant, Cambridge Biomedical Campus, Cambridge, United Kingdom.
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom.
Department of Haematology, Barts Health National Health Service Trust, London, United Kingdom.
Katharine Dormandy Haemophilia Centre and Thrombosis Unit, Royal Free London NHS Foundation Trust, London, United Kingdom.
Department of Haematology, University College London Cancer Institute, London, United Kingdom.
Institut Hospitalo-Universitaire L'Institut de Rythmologie et Modelisation Cardiaque, Hopital Xavier Arnozan, Pessac, France.
Département d'Hématologie, Assistance-Publique Hôpitaux de Paris, Centre de Référence des Pathologies Plaquettaires, Hôpital Armand Trousseau, Paris, France.
INSERM, Villejuif, France.
Cardiovascular Epidemiology Unit of the Medical Research Council/British Heart Foundation, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom; and.
Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom.


Mutations in NBEAL2, the gene encoding the scaffolding protein Nbeal2, are causal of gray platelet syndrome (GPS), a rare recessive bleeding disorder characterized by platelets lacking α-granules and progressive marrow fibrosis. We present here the interactome of Nbeal2 with additional validation by reverse immunoprecipitation of Dock7, Sec16a, and Vac14 as interactors of Nbeal2. We show that GPS-causing mutations in its BEACH domain have profound and possible effects on the interaction with Dock7 and Vac14, respectively. Proximity ligation assays show that these 2 proteins are physically proximal to Nbeal2 in human megakaryocytes. In addition, we demonstrate that Nbeal2 is primarily localized in the cytoplasm and Dock7 on the membrane of or in α-granules. Interestingly, platelets from GPS cases and Nbeal2-/- mice are almost devoid of Dock7, resulting in a profound dysregulation of its signaling pathway, leading to defective actin polymerization, platelet activation, and shape change. This study shows for the first time proteins interacting with Nbeal2 and points to the dysregulation of the canonical signaling pathway of Dock7 as a possible cause of the aberrant formation of platelets in GPS cases and Nbeal2-deficient mice.

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