Disabled-2 Is a Negative Regulator of Integrin αIIbβ3-mediated Fibrinogen Adhesion and Cell Signaling

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

doi:10.1074/jbc.m402540200

Cited by 54 publications

(73 citation statements)

References 46 publications

(54 reference statements)

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“…Like other adaptor proteins, Dab2 contains protein-binding domains and phosphorylation sites, and lacks catalytic domains [7]. Dab2 contains an amino-terminal phosphotyrosine-binding (PTB) domain and a carboxy-terminal prolinerich domain (PRD), which have been shown to associate with the low-density lipoprotein receptor [3,8], myosin VI [9], the integrin b subunits [10][11][12], TAK1 [5], Grb2 [1,2], c-Src [13], Smad2/3 [14], DIP1/2 [15], Dvl-3 [16], and axin [17]. These interactions have been shown to modulate protein trafficking, cytoskeleton organization, cell adhesion and migration, and cell signaling of various receptor protein-tyrosine kinases.…”

Section: Introductionmentioning

confidence: 99%

Morphogenesis of human endothelial cells is inhibited by DAB2 via Src

et al. 2008

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Disabled-2 (DAB2) is an adaptor protein implicated in signal transduction pathways and in protein traffic regulation. Here, we show that DAB2 is highly expressed in human endothelial cells. DAB2 silencing in endothelial cells by lentiviral-mediated small hairpin RNA expression affects cell migration and differentiation into capillary-like structures while increasing cell proliferation and viability. DAB2 knockdown causes activation of the Src-FAK signal pathway, extracellular-signal regulated kinase and c-Jun NH 2 -terminal kinase activation, and inhibition of p38 phosphorylation. In DAB2 silenced endothelial cells, pharmacological inhibition of Src with its specific inhibitor PP2 abolishes focal adhesion kinase activation and restores differentiation of endothelial cells. These results suggest that DAB2, via Src and focal adhesion signaling, plays a role in human endothelial cell function.

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Section: Introductionmentioning

confidence: 99%

Morphogenesis of human endothelial cells is inhibited by DAB2 via Src

et al. 2008

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“…Thus, it is possible that similar to integrin binding to the epidermal growth factor receptor and potentiating its signaling, Dab2 may serve to couple or bridge the TGF␤ receptor complex with integrins, thereby modulating TGF␤ and integrin signaling. In a recent study, Huang et al (44) report on the role of Dab2 during 12-O-tetradecanoylphorbol-13-acetate-induced megakaryocytic differentiation. They also implicate an important integrin modulatory role for Dab2 during differentiation; however, in contrast to our results, they show that Dab2 inhibits adhesion and integrin activation.…”

Section: Dab2 In Tgf␤-induced Emtmentioning

confidence: 99%

Disabled-2 (Dab2) Is Required for Transforming Growth Factor β-induced Epithelial to Mesenchymal Transition (EMT)

Prunier¹,

Howe

2005

Journal of Biological Chemistry

123

103

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Transforming growth factor ␤ (TGF␤) induces an epithelial to mesenchymal transition (EMT) during both physiological and pathological processes; however, the mechanism underlying this transition is not fully eluci- Epithelial to mesenchymal transition (EMT)1 is a fundamental multistep process that occurs during both physiological and pathological states (1, 2). By allowing cells to detach from the epithelial tissue where they originate and to migrate, such transitions are necessary for proper embryonic development. However, they also provide a way for epithelium-derived tumors from a benign stage to become invasive and metastasize throughout the body. It has been demonstrated that there is commonality in the signaling pathways regulating EMT during both embryonic development and tumor progression, suggesting that similar molecular mechanisms underlie these processes and raising the possibility that tumor metastasis might simply be considered as a reactivation of some aspects of the embryonic program of EMT.The process of EMT requires loss of cell-cell interaction and acquisition of fibroblastic morphology with increased expression of mesenchymal markers, such as N-cadherin (3). Among growth factors that can promote this structural conversion, transforming growth factor ␤ (TGF␤) has been well characterized as an important inducer of EMT during development as well as during cancerogenesis (4). Indeed, although TGF␤ is considered a tumor suppressor during the first stage of tumorigenesis, principally through its ability to cause growth arrest and apoptosis in many non-transformed epithelial cell types, numerous reports show that TGF␤ can also promote tumor progression, particularly through its ability to promote EMT (4, 5). Moreover, it has been shown that blocking TGF␤ signaling in transgenic mice that develop multifocal metastatic mammary tumors reduces mammary tumor intravasation and lung metastasis and increases mammary tumor cell apoptosis (6).TGF␤ exerts its biological effects by inducing the formation of a heteromeric complex composed of type I and type II serine/ threonine kinases receptors. The activated receptor complex, in turn, phosphorylates and activates the receptor-regulated

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“…Accordingly, DAB2 acts to control a variety of cellular processes including growth factor and hormone signaling, endocytosis and cell-adhesive function (Xu et al, 1998;Inoue et al, 2002;Morris et al, 2002;Kowanetz et al, 2003;Zhou et al, 2003). In the hematopoietic system, DAB2 is abundantly expressed in human platelets (Huang et al, 2004) and is upregulated through platelet-derived growth factor (PDGF) autocrine signaling (Tseng et al, 2005) during megakaryocytic differentiation of human leukemic cell lines and CD34 + hematopoietic pluripotent stem cells (Tseng et al, 2001;Tseng et al, 2003;Huang et al, 2004). DAB2 negatively regulates ␣IIb␤3-integrin-mediated fibrinogen adhesion and cell signaling in a S24-phosphorylation-dependent manner that promotes DAB2 membrane translocation and the subsequent interaction with the ␤3 integrin cytoplasmic tail (Huang et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

“…Like other adapter proteins, DAB2 elicits its function through interaction with other cellular factors. This is mainly mediated through the N-terminal phosphotyrosine binding (PTB) domain, the aspartic-acid-proline-phenylalanine (DPF) motif and the Cterminal proline-rich region (Calderwood et al, 2003;Huang et al, 2004;Wang et al, 2002;Hocevar et al, 2001;Hocevar et al, 2003). Accordingly, DAB2 acts to control a variety of cellular processes including growth factor and hormone signaling, endocytosis and cell-adhesive function (Xu et al, 1998;Inoue et al, 2002;Morris et al, 2002;Kowanetz et al, 2003;Zhou et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

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

Huang

Cheng

Stern

et al. 2006

Journal of Cell Science

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Platelet aggregation plays a pivotal role in the haemostatic process and is involved in the pathological counterpart of arterial thrombosis. We have shown that the adapter protein disabled-2 (DAB2) is expressed abundantly in platelets. In this study, DAB2 was found to distribute in the platelet ␣ ␣-granules and was released from the granular compartment upon platelet activation. The secreted DAB2 binds to the extracellular region of ␣ ␣IIb␤ ␤3 integrin on the platelet surface through the phosphotyrosine-binding domain. The DAB2-platelet interactions result in the inhibition of agonist-induced platelet aggregation with the exception of thrombin, a DAB2 protease that renders DAB2 inactive. Biochemical and mutational analysis revealed that the DAB2 cell-adhesion Arg-Gly-Asp (RGD) motif (amino acid residues 64-66) and the ␣ ␣IIb-integrin-fibrinogenbinding region (amino acid residues 171-464) are important for the DAB2-platelet interactions. Such interactions compete for the binding of ␣ ␣IIb integrin with fibrinogen and provide a mechanism for DAB2 to inhibit platelet aggregation. Accordingly, the synthetic RGD-motifcontaining DAB2 peptide PDARGDKM also elicited antiplatelet aggregation activity. These findings demonstrate for the first time that DAB2 is an ␣ ␣IIb-integrin-binding protein that plays a novel role in the control of plateletfibrinogen interactions and platelet aggregation.Key words: Disabled-2, Fibrinogen, ␣IIb␤3 Integrin, Platelet aggregation, RGD motif SummaryDisabled-2 is a novel ␣ ␣IIb-integrin-binding protein that negatively regulates platelet-fibrinogen interactions and platelet aggregation

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Disabled-2 Is a Negative Regulator of Integrin αIIbβ3-mediated Fibrinogen Adhesion and Cell Signaling

Cited by 54 publications

References 46 publications

Morphogenesis of human endothelial cells is inhibited by DAB2 via Src

Morphogenesis of human endothelial cells is inhibited by DAB2 via Src

Disabled-2 (Dab2) Is Required for Transforming Growth Factor β-induced Epithelial to Mesenchymal Transition (EMT)

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

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