Structure, Sulfatide Binding Properties, and Inhibition of Platelet Aggregation by a Disabled-2 Protein-derived Peptide

Xiao, S. Y.; Charonko, John; Fu, Xiangping; Salmanzadeh, Alireza; Davalos, Rafael V.; Vlachos, Pavlos P.; Finkielstein, Carla V.; Capelluto, Daniel G. S.

doi:10.1074/jbc.m112.385609

Cited by 17 publications

(47 citation statements)

References 60 publications

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“…As a promising therapeutic peptide (Fig. ), Dab2 SBM exhibits an anti‐aggregatory platelet activity comparable with that described for Arg‐Gly‐Asp‐Ser (RGDS), a fibrinogen‐derived peptide .…”

Section: Introductionmentioning

confidence: 69%

Disabled-2: A modular scaffold protein with multifaceted functions in signaling

Finkielstein

Capelluto

2015

Inside the Cell

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Disabled‐2 (Dab2) is a multimodular scaffold protein with signaling roles in the domains of cell growth, trafficking, differentiation, and homeostasis. Emerging evidences place Dab2 as a novel modulator of cell–cell interaction; however, its mode of action has remained largely elusive. In this review, we highlight the relevance of Dab2 function in cell signaling and development and provide the most recent and comprehensive analysis of Dab2's action as a mediator of homotypical and heterotypical interactions. Accordingly, Dab‐2 controls the extent of platelet aggregation through various motifs within its N‐terminus. Dab2 interacts with the cytosolic tail of the integrin receptor blocking inside‐out signaling, whereas extracellular Dab2 competes with fibrinogen for integrin αIIbβ3 receptor binding and, thus, modulates outside‐in signaling. An additional level of regulation results from Dab2's association with cell surface lipids, an event that defines the extent of cell–cell interactions. As a multifaceted regulator, Dab2 acts as a mediator of endocytosis through its association with the [FY]xNPx[YF] motifs of internalized cell surface receptors, phosphoinositides, and clathrin. Other emerging roles of Dab2 include its participation in developmental mechanisms required for tissue formation and in modulation of immune responses. This review highlights the various novel mechanisms by which Dab2 mediates an array of signaling events with vast physiological consequences.

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Section: Introductionmentioning

confidence: 69%

Disabled-2: A modular scaffold protein with multifaceted functions in signaling

Finkielstein

Capelluto

2015

Inside the Cell

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“…A recent report indicated that sulfatide-laminin binding can initiate basement membrane assembly and signaling ( 9 ). Sulfatide expressed on cell surface exerts biological functions through mediating interactions with various proteins, such as laminin, hepatocyte growth factor, and disabled-2 ( 34 ). Furthermore, the expression and distribution of sulfatide are often altered during development and oncogenic transformation ( 35 ).…”

Section: Discussionmentioning

confidence: 99%

Regulation of integrin αV subunit expression by sulfatide in hepatocellular carcinoma cells

Dong

Shi

et al. 2013

Journal of Lipid Research

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This article is available online at http://www.jlr.org linked ␣ -and ␤ -subunit, with each subunit having a large extracellular domain, a single membrane-spanning domain, and a short, noncatalytic cytoplasmic tail. Integrins seem to be the major receptors by which cells attach to components of the extracellular matrix (ECM), such as vitronectin, etc. ( 4 ), and are involved in the metastasis signaling of hepatocellular carcinoma (HCC) ( 5 ).The integrin ␣ V subunit associates with one of fi ve integrin ␤ subunits, ␤ 1, ␤ 3, ␤ 5, ␤ 6, or ␤ 8, to form fi ve distinct ␣ V ␤ heterodimers ( 6 ). The integrin ␣ V ␤ heterodimers on the cell surface interact with cell adhesive proteins, such as collagen, fi brinogen, fi bronectin, and vitronectin. These interactions play an important role in cell adhesion or migration, especially in tumor metastasis. Integrins increase in invasive tumors and distant metastases, characterize the metastatic phenotype, and play a key role in tumor metastasis ( 7,8 ). Many studies have documented marked differences in the surface expression and distribution of integrins between malignant tumors and preneoplastic tissues. For example, the integrin ␣ V ␤ 3 complex is strongly expressed in the invasive front cells of malignant melanoma and angiogenic blood vessels, but it is weakly expressed on preneoplastic melanomas and quiescent blood vessels ( 9 ). Also, it has been demonstrated that ␣ V ␤ 3 integrin is specifi cally required to sustain neovascularization induced in vivo by fibroblast growth factor-2 ( 10 ). Integrin ␣ V ␤ 3 physically associates with phosphorylated and activated insulin-like growth factor receptor, and it may be involved in the HCC cell migration and progression ( 11 ). Furthermore, inducing the expression of the integrin ␣ V ( 7 ) or ␤ 3 ( 12 ) subunit in melanoma cells increases their metastatic potential. Integrins have been implicated as very important adhesion molecules that are involved in multiple physiological processes, such as cell adhesion, proliferation, and survival ( 1-3 ). Each integrin generally consists of a noncovalently Abstract Integrin is important in migration and

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“…Disabled-2 (Dab2) is an adaptor protein expressed in various cell types, including megakaryocytes and platelets [10][11][12]. Dab2 regulates receptor-mediated endocytosis, embryonic development, differentiation, signal transduction, the immune response and platelet activation through interactions with a variety of molecules [10,[12][13][14][15][16][17][18][19][20][21][22][23][24][25]. Dab2 has at least two alternative splicing isoforms (p82 and p59) [26,27].…”

Section: Introductionmentioning

confidence: 99%

Functional links between Disabled‐2 Ser723 phosphorylation and thrombin signaling in human platelets

Tsai

Chien

Liao

et al. 2017

Journal of Thrombosis and Haemostasis

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Background Disabled-2 (Dab2) is a platelet protein that is functionally involved in thrombin signaling in mice. It is unknown whether or not Dab2 undergoes phosphorylation during human platelet activation. Objectives To investigate the phosphorylation status of Dab2 and its functional consequences in thrombin-stimulated human platelets. Methods Dab2 was immunoprecipitated from resting and thrombin-stimulated platelet lysates for differential isotopic labeling. After enrichment of the phosphopeptides, the phosphorylation sites were analyzed by mass spectrometry. The corresponding phospho-specific antibody was generated. The protein kinases responsible for and the functional significance of Dab2 phosphorylation were defined by the use of signaling pathway inhibitors/activators, protein kinase assays, and various molecular approaches. Results Dab2 was phosphorylated at Ser227, Ser394, Ser401 and Ser723 in thrombin-stimulated platelets, with Ser723 phosphorylation being the most significantly increased by thrombin. Dab2 was phosphorylated by protein kinase C at Ser723 in a G -dependent manner. ADP released from the stimulated platelets further activated the G -dependent pathway to sustain Ser723 phosphorylation. The Cbl-interacting protein of 85 kDa (CIN85) bound to Dab2 at a motif adjacent to Ser723 in resting platelets. The consequence of Ser723 phosphorylation was the dissociation of CIN85 from the Dab2-CIN85 complex. These molecular events led to increases in fibrinogen binding and platelet aggregation in thrombin-stimulated platelets by regulating α β activation and ADP release. Conclusions Dab2 Ser723 phosphorylation is a key molecular event in thrombin-stimulated inside-out signaling and platelet activation, contributing to a new function of Dab2 in thrombin signaling.

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Structure, Sulfatide Binding Properties, and Inhibition of Platelet Aggregation by a Disabled-2 Protein-derived Peptide

Cited by 17 publications

References 60 publications

Disabled-2: A modular scaffold protein with multifaceted functions in signaling

Disabled-2: A modular scaffold protein with multifaceted functions in signaling

Regulation of integrin αV subunit expression by sulfatide in hepatocellular carcinoma cells

Functional links between Disabled‐2 Ser723 phosphorylation and thrombin signaling in human platelets

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