Volume 14 Supplement 1
The adaptor protein Disabled-2: new insights into platelet biology and integrin signaling
© The Author(s). 2016
Published: 4 October 2016
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.
KeywordsDisabled-2 Integrin αIIbβ3 Megakaryocyte Platelet
Platelets are the second most abundant blood cells and are derived from the cytoplasm of megakaryocytes . The crucial role of platelet in haemostasis and thrombosis has prompted extensive attentions on unveiling the underlying mechanisms of platelet activation induced by soluble agonists [2–4]. Platelet activation is mainly mediated by binding of ligands to the membrane receptors such as the immunoglobulin family of glycoproteins for collagen and the G-protein coupled receptors for thrombin, thromboxane A2 (TXA2) and adenosine diphosphate (ADP) . Collagen interacts with glycoprotein VI which contains an immunoreceptor tyrosine-based activation motif (ITAM). The ITAM is phosphoryated by two Src kinases (Lyn and Fyn) and recruits the protein tyrosine kinase Syk to the plasma membrane for phosphorylation of downstream substrates at the tyrosine residue that are essential for platelet activation . Other soluble agonists such as thrombin, TXA2 and ADP bind to the respective G protein-coupled receptors and cause an increase in intracellular calcium and protein kinase C (PKC) activity, Rho activation, inhibition of adenylyl cyclase and activation of phosphoinositide 3-kinase-Akt through the Gαq-, Gα12/13-, Gαi-, and Gβγ-dependent pathway, respectively [5, 6]. The inside-out signaling induced by different platelet agonists activates integrin αIIbβ3 followed by the binding of fibrinogen to integrin αIIbβ3 and activation of outside-in signaling. These intracellular events ultimately lead to platelet activation, secretion and aggregation . Despite extensive studies, the underlying mechanisms of platelet signaling networks still wait to be fully elucidated.
Adaptor protein is a type of proteins mediating protein-protein and protein-lipid interactions. It has been clearly demonstrated that adaptor proteins are essential for coupling membrane receptors to intracellular signaling pathways and the assembly of signaling scaffolds within the cells. Many adaptor proteins expressed in the platelets are involved in inside-out and outside-in signaling of integrin during platelet activation . Disabled-2 (Dab2) is a newly identified adaptor protein that is known to express in megakaryocytes and platelets from a variety of species [9, 10]. The current knowledge about the roles of Dab2 in megakaryocytic differentiation and platelet signaling is still in the beginning. This review will focus on the expression and functional aspects of Dab2 in megakaryocytic differentiation, platelet activation and integrin signaling.
Discovery and the protein properties of Dab2
Dab2 is a phosphoprotein with several phosphoryation sites having been identified. Dab2 is phosphorylated at serine residues in murine macrophage cell line in response to mitogenic stimulation by CSF-1 . Dab2-Ser24 is phosphorylated by PKCβII, γ and δ but not by casein kinase II, playing a critical role in the inhibition of 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced AP-1 activity and integrin activation [33, 40]. Dab2 is hyperphosphorylated by the cyclin-dependent serine/threonine kinase Cdc2 during the mitosis phase of the cell cycle in HeLa S3 cells . The phosphorylated Dab2 interacts with the peptidylprolyl isomerase Pin1 that facilitates Dab2 dephosphorylation immediately after the end of mitosis phase . Similarly, Akt interacts with PRD domain of Dab2 and phosphorylates Ser448/Ser449 to regulate albumin endocytosis and mediate albumin uptake in proximal tubule [25, 43]. These distinct protein properties facilitate the involvement of Dab2 in diverse signaling network in response to extracellular responses.
Expression pattern of Dab2 in megakaryocytes and platelets
Dab2 expression and function in megakaryocytes and platelets
Reported Dab2 expression/function
Human K562 cells
Increased Dab2 expression during TPA-induced megakaryocytic differentiation
Positive regulation of fibrinogen uptake
Dab2 interacts with integrin β3 and inhibits integrin αIIbβ3 activation
Human CD34+ stem cells
Increased Dab2 expression during TPO-induced megakaryocytic differentiation
Mouse embryonic stem cells/OP9 co-culture
Increased Dab2 expression during mesodermal and megakaryocytic differentiation
Dab2 is required for mesodermal differentiation
High expression of p82-Dab2 in the cytoplasm and α-granule
Dab2 interacts with the cytoplamic tail of platelet integrin
Secreted Dab2 interacts with integrin αIIb and sulfatide; is a substrate of thrombin
Dab2 regulates fibrinogen binding and homotypic and heterotypic platelet interactions
Low expression of p59-Dab2
Dab2-deficient mice display a prolonged bleeding time and impaired thrombus formation
Dab2 is required for platelet aggregation, fibrinogen uptake, RhoA-ROCK activation, ADP release and integrin αIIbβ3 activation stimulated by low concentration of thrombin
The evolutionary roles for an increase in Dab2 expression from mouse to rat and human platelets and the species-specific expression of Dab2 isoforms are not yet understood. Distinctive functions of p82-Dab2 and p59-Dab2 have been unveiled in several studies. p82-Dab2 is known to regulate receptor-mediated endocytosis, while p59-Dab2 is a transcriptional regulator when the F9 cells are undergone differentiation [18, 20, 45, 46]. Knock-in expression of p59-Dab2 only partially compromises the absence of Dab2 in the Dab2-knockout mice . The increased expression of p82-Dab2 protein in human platelets may fine tune platelet response to soluble agonists and provide a superior way to prevent excessive blood loss in the large mammals. Future study using an in vivo animal model expressing human platelet p82-Dab2 should provide new insight for the aforementioned hypothesis.
Dab2 functions in megakaryocytic differentiation and platelet signaling
Dab2 is present in the cytoplasm and α-granules of human platelets and is released from the platelets in response to platelet activation . Dab2 is shown in a number of studies playing a pivotal role in the activation of human platelets. Dab2 interacts with the cytoplasmic tail of the platelet integrin and regulates inside-out signaling . On the other hand, Dab2 released from the α-granules is able to bind the extracellular region of αIIbβ3 integrin through the Dab2 cell-adhesion Arg-Gly-Asp (RGD) motif (amino acid residues 64–66) and the fibrinogen binding region of integrin αIIb. Such interactions compete for the integrin αIIb-fibrinogen interactions and inhibit platelet aggregation induced by soluble agonists except thrombin. Thrombin renders Dab2 inactive by cleavage of Dab2 at the amino acid residue 64 . Notably, the action of thrombin on Dab2 cleavage is suppressed when Dab2 binds to the phospholipid sulfatide through four positively charged residues (Lys25, Lys49, Lys51, and Lys53) located at the PTB domain . Hence, two pools of Dab2 is present at the outer surface of the platelet plasma membrane, one at the sulfatide-bound and the other at the integrin αIIbβ3-bound states. The balance between these two Dab2 states is involved in the regulation of clotting reaction, platelet aggregation and the interactions of platelet and fibrinogen in response to stimulation by platelet agonists [10, 47–49].
Megakaryocyte/platelet lineage-restricted Dab2 knockout (Dab2-/-) mice have been generated by using the Cre-loxP transgenic system driven by the platelet factor 4 promoter to elucidate Dab2 functions in vivo . Dab2-/- platelets, when stimulated by low concentrations of thrombin, are defective in platelet aggregation, clot retraction, and spreading on fibrinogen. The functional imperfection of Dab2-/- platelets is related to the defective responses to thrombin-induced RhoA-ROCKII and Akt-mTOR activation, ADP release and integrin αIIbβ3 activation . Although Dab2 elicits a restrictive function to the murine platelets stimulated by low concentrations of thrombin, defective Dab2 expression has profound effects on hemostasis and thrombosis in vivo. This is evidenced by the observations that bleeding time is prolonged and thrombus formation is impaired in the Dab2-/- mice. These findings are consistent with the perception that protease-activated receptors (PAR) 3- and PAR4-deficient mice, despite eliciting a partial decrease in thrombin-induced platelet aggregation, are impaired in hemostasis and are protected against thrombosis [50, 51]. These studies support the notion that Dab2 is a key regulator in hemostasis and thrombosis.
The consensuses, controversies and future prospects
The study linking Dab2 functions with megakaryocytic differentiation, platelet signaling and integrin activation was first reported 15 years ago . The studies up-to-date support extensively that Dab2 is a regulator of megakaryocytic differentiation and platelet function. Nevertheless, distinctive functions of Dab2 in human and mouse megakaryocytes and platelets are noted. Knockdown of Dab2 results in an increase in αIIbβ3 activation and cell adhesion to fibrinogen in the K562 cells . Dab2 is, however, required for murine platelet aggregation and integrin αIIbβ3 activation when the platelets are stimulated by low concentrations of thrombin . Dab2 negatively regulates human platelet-fibrinogen interaction and platelet aggregation induced by soluble agonists except thrombin [10, 47–49]. The complexity in the abundance and species-specific expression of Dab2 isoforms and the diverse thrombin signaling in human and murine platelets [6, 9] likely contribute to the reported heterogeneity of Dab2 function. Alternatively, the discrepancy in these findings could be due to the different assay systems being used in these studies. In the studies of human platelets, recombinant Dab2 protein was the main tool for analyzing the effects of Dab2 function on platelet response by in vitro experiments [10, 47–49]. There are no Dab2 mutants or Dab2-deficient human platelets available for in vivo study. On the other hand, Dab2-deficient murine platelets have been generated for analysis of Dab2 function in vivo . An animal model expressing human platelet Dab2 should help us to understand the distinctive Dab2 functions in human and murine platelets.
Dab2 is known as a phosphoprotein in a variety of cellular processes [12, 25, 33, 40–43]. Due to the lack of appropriate tools, the physiological functions of Dab2 phosphorylation in platelet signaling have not yet been elucidated. We have addressed these issues in our recent work and revealed that Dab2 is phosphorylated during agonist-stimulated human platelet activation (unpublished data). With the new tools such as CRISPR and TALEN [52–55] in the generation of genetically modified animals, the progress in gaining new insights into the signaling network involving Dab2 expression and phosphorylation in megakaryocyte, platelet biology and integrin signaling is expected to accelerate.
Multiple functions of platelets in hemostasis, thrombosis, immunology, cancer progression, microorganism infections call for considerable attention on understanding how the activated platelets transmit intracellular signal to elicit their roles in different biological responses. Extensive evidence from the studies in the past decades demonstrates that Dab2 is a key regulator of platelet signaling, in particular, the endocytosis and the activation of thrombin-stimulated inside-out signaling of platelet integrin. With the complicated nature of the signaling network within megakaryocytes and platelets, the definitive roles of Dab2 in megakaryocytic differentiation, platelet activation and integrin signaling remain to be explored further.
Embryonic stem cells
Immunoreceptor tyrosine-based activation motif
Protein kinase C
Proline rich domain
Phosphotyrosine binding domain
- TXA2 :
Publication fees for this article have been funded by APSTH 2016.
This article has been published as part of Thrombosis Journal Volume 14 Supplement 1, 2016. The full contents of the supplement are available at https://thrombosisjournal.biomedcentral.com/articles/supplements/volume-14-supplement-1
The work performed in the authors’ laboratory was supported in part by the Ministry of Science and Technology grants MOST102-2628-B-182-009-MY3, MOST102-2628-B-182-010-MY3, MOST105-2320-B-182-029-MY3, MOST105-2320-B-182-030, the Chang Gung Memorial Hospital grants (CMRPD1C0551-3, CMRPD1B0391-3, CMRPD1E0181-3, and BMRP466), and the Chang Gung Molecular Medicine Research Center grant (EMRPD1E1491) to C.-P. Tseng; the Ministry of Science and Technology post-doctoral fellowship grants 104-2811-B-182-004 and 104-2811-B-182-006 to H.-J. Tsai.
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HJT and CPT contributed in the conception and the design of the article and have given final approval of the version to be submitted.
The authors declare that they have no competing interests.
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