Disabled-2 is a novel αIIb-integrin-binding protein that negatively regulates platelet-fibrinogen interactions and platelet aggregation

Huang, Chien‐Ling; Cheng, Ju Chien; Stern, Arnold; Hsieh, Jer Tsong; Liao, Chia-Shu; Tseng, Ching Ping

doi:10.1242/jcs.03195

Cited by 35 publications

(68 citation statements)

References 45 publications

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“…These include clathrin (14), the adaptor complex 2 (AP2 (20)), NPXY-containing cargo (13)(14)(15)(16)20), and myosin VI (18,(23)(24)(25), all related to its endocytic functions, and Dab2-interacting protein (Dab2IP (1)), Src (6), Grb (4), CIN85 (26), axin (7), Smads, and the transforming growth factor ␤ (TGF-␤) receptors (9,10), which enable the signalmodulating potential of Dab2. Dab2 also binds directly to integrins and may thus coordinate changes to cell adhesion, cell motility, membrane trafficking, and signaling (11,(27)(28)(29)(30). Taken together, the current picture suggests that the function of Dab2 is regulated by intracellular localization, by association with specific interacting factors, and possibly by posttranslational modification.…”

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confidence: 88%

Negative Regulation of the Endocytic Adaptor Disabled-2 (Dab2) in Mitosis

Chetrit

Barzilay

Horn

et al. 2011

Journal of Biological Chemistry

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Mitotic cells undergo extensive changes in shape and size through the altered regulation and function of their membrane trafficking machinery. Disabled 2 (Dab2), a multidomain cargo-specific endocytic adaptor and a mediator of signal transduction, is a potential integrator of trafficking and signaling. Dab2 binds effectors of signaling and trafficking that localize to different intracellular compartments. Thus, differential localization is a putative regulatory mechanism of Dab2 function. Furthermore, Dab2 is phosphorylated in mitosis and is thus regulated in the cell cycle. However, a detailed description of the intracellular localization of Dab2 in the different phases of mitosis and an understanding of the functional consequences of its phosphorylation are lacking. Here, we show that Dab2 is progressively displaced from the membrane in mitosis. This phenomenon is paralleled by a loss of co-localization with clathrin. Both phenomena culminate in metaphase/ anaphase and undergo partial recovery in cytokinesis. Treatment with 2-methoxyestradiol, which arrests cells at the spindle assembly checkpoint, induces the same effects observed in metaphase cells. Moreover, 2-methoxyestradiol also induced Dab2 phosphorylation and reduced Dab2/clathrin interactions, endocytic vesicle motility, clathrin exchange dynamics, and the internalization of a receptor endowed with an NPXY endocytic signal. Serine/threonine to alanine mutations, of residues localized to the central region of Dab2, attenuated its phosphorylation, reduced its membrane displacement, and maintained its endocytic abilities in mitosis. We propose that the negative regulation of Dab2 is part of an accommodation of the cell to the altered physicochemical conditions prevalent in mitosis, aimed at allowing endocytic activity throughout the cell cycle.

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mentioning

confidence: 88%

Negative Regulation of the Endocytic Adaptor Disabled-2 (Dab2) in Mitosis

Chetrit

Barzilay

Horn

et al. 2011

Journal of Biological Chemistry

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“…MRP4 and LAMP2 for immature and mature DGs, platelet factor-4 (PF-4) for AGs 35 ; and Rab7a and Rab32 for cytosol, vesicles, and immature DGs. The DG markers LAMP2 and MRP4 coelute in F6 to F9, suggesting these fractions contain an heterogeneous mixture of DGs at different levels of maturation.…”

Section: Dgs Can Be Studied Biochemically In Meg-01 Cellsmentioning

confidence: 99%

Mechanism of platelet dense granule biogenesis: study of cargo transport and function of Rab32 and Rab38 in a model system

Ambrosio

Boyle

Pietro

2012

Blood

113

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Dense granules are important in platelet aggregation to form a hemostatic plug as evidenced by the increased bleeding time in mice and humans with dense granule deficiency. Dense granules also are targeted by antiplatelet agents because of their role in thrombus formation. Therefore, the molecular understanding of the dense granule and its biogenesis is of vital importance. In this work, we establish a human megakaryocytic cell line (MEG-01) as a model system for the study of dense granule biogenesis using a variety of cell biology and biochemical approaches. Using this model system, we determine the late endocytic origin of these organelles by colocalization of the internalized fluid phase marker dextran with both mepacrine and transmembrane dense granule proteins. By mistargeting of mutant dense granule proteins, we demonstrate that sorting signals recognized by adaptor protein-3 are necessary for normal transport to dense granules.

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“…Immunofluorescence staining Immunofluorescence staining of reelin was performed as described previously with some modifications [19]. The washed platelets were cytospun on a glass coverslip, fixed with 3.7% formaldehyde solution at room temperature for 15 min and permeabilized with 0.1% Triton X-100 at 4°C for 10 min.…”

Section: Expression and Purification Of Recombinant Reelinmentioning

confidence: 99%

Reelin is a platelet protein and functions as a positive regulator of platelet spreading on fibrinogen

Tseng

Huang

Chong

et al. 2009

Cell. Mol. Life Sci.

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Abnormalities of platelet functions have been linked to reelin-impaired neuronal disorders. However, little attention has been given to understanding the interplay between reelin and platelet. In this study, reelin was found to present in the human platelets and megakaryocyte-like leukemic cells. Reelin-binding assays revealed that extracellular reelin can interact with platelets through the receptor belonging to the low density lipoprotein receptor gene family. The reelin-to-platelet interactions enhance platelet spreading on fibrinogen concomitant with the augmentation of lamellipodia formation and F-actin bundling. In contrast, reelin has no effect on integrin alphaIIbbeta3 activation and agonist-induced platelet aggregation. Molecular analysis revealed that the up-regulation of Rac1 activity and the inhibition of protein kinase C delta-Thr505 phosphorylation are important for reelin-mediated enhancement of platelet spreading on fibrinogen. These findings demonstrate for the first time that reelin is present in platelets and the reelin-to-platelet interactions play a novel role in platelet signaling and functions.

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Disabled-2 is a novel αIIb-integrin-binding protein that negatively regulates platelet-fibrinogen interactions and platelet aggregation

Cited by 35 publications

References 45 publications

Negative Regulation of the Endocytic Adaptor Disabled-2 (Dab2) in Mitosis

Negative Regulation of the Endocytic Adaptor Disabled-2 (Dab2) in Mitosis

Mechanism of platelet dense granule biogenesis: study of cargo transport and function of Rab32 and Rab38 in a model system

Reelin is a platelet protein and functions as a positive regulator of platelet spreading on fibrinogen

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