The adaptor protein Disabled-2: new insights into platelet biology and integrin signaling.

Multiple functions of platelets in various physiological and pathological conditions have prompted considerable attention on understanding how platelets are generated and activated. Of the adaptor proteins that are expressed in megakaryocytes and platelets, Disabled-2 (Dab2) has been demonstrated in the past decades as a key regulator of platelet signaling. Dab2 has two alternative splicing isoforms p82 and p59. However, the mode of Dab2's action remains to be clearly defined. In this review, we highlight the current understanding of Dab2 expression and function in megakaryocytic differentiation, platelet activation and integrin signaling. Accordingly, Dab2 is upregulated when the human K562 cells, human CD34 hematopoietic stem cells, and murine embryonic stem cells were undergone megakaryocytic differentiation. Appropriate level of Dab2 expression is essential for fate determination of mesodermal and megakaryocytic differentiation. Dab2 is also shown to regulate cell-cell and cell-fibrinogen adhesion, integrin αIIbβ3 activation, fibrinogen uptake, and intracellular signaling of the megakaryocytic cells. In human platelets, p82 is the sole Dab2 isoform present in the cytoplasm and α-granules. Dab2 is released from the α-granules and forms two pools of Dab2 on the outer surface of the platelet plasma membrane, one at the sulfatide-bound and the other at integrin αIIbβ3-bound forms. The balance between these two pools of Dab2 controls the extent of clotting reaction, platelet-fibrinogen interactions and outside-in signaling. In murine platelets, p59 is the only Dab2 isoform and is required for platelet aggregation, fibrinogen uptake, RhoA-ROCK activation, adenosine diphosphate release and integrin αIIbβ3 activation stimulated by low concentration of thrombin. As a result, the bleeding time is prolonged and thrombus formation is impaired for the megakaryocyte lineage-restricted Dab2 deficient mouse. Although discrepancies of Dab2 function and isoform expression are noted between human and murine platelets, the studies up-to-date define Dab2 playing a pivotal role in integrin signaling and platelet activation. With the new tools such as CRISPR and TALEN in the generation of genetically modified animals, the progress in gaining new insights into the functions of Dab2 in megakaryocyte and platelet biology is expected to accelerate.