Platelets
Institute of Experimental Biomedicine I, University Hospital Würzburg and Rudolf Virchow Center, University of Würzburg, Würzburg, Germany.
Published: August 2020
Platelets are essential for normal hemostasis; however, pathological conditions can also trigger unwanted platelet activation precipitating thrombosis and ischemic damage of vital organs such as the heart or brain. (GP)VI- and (CLEC-2)-mediated (hem) (ITAM) signaling represents a major pathway for platelet activation. The two members of the (Grb2) family of adapter proteins expressed in platelets - Grb2 and (Gads) - are part of the hem(ITAM) signaling cascade by forming an adapter protein complex with (LAT). To date, a possible functional redundancy between these two adapters in platelet activation has not been investigated. We here generated megakaryocyte- and platelet-specific Grb2/Gads (DKO) mice and analyzed their platelet function in vitro and in vivo. The DKO platelets exhibited virtually abolished (hem)ITAM signaling whereas only partial defects were seen in Grb2 or Gads single-deficient platelets. This was based on impaired phosphorylation of key molecules in the (hem)ITAM signaling cascade and translated into impaired hemostasis and partially defective arterial thrombosis, thereby exceeding the defects in either Grb2 KO or Gads KO mice. Despite this severe (hem)ITAM signaling defect, CLEC-2 dependent regulation of blood-lymphatic vessel separation was not affected in the DKO animals. These results provide direct evidence for critically redundant roles of Grb2 and Gads for platelet function in hemostasis and thrombosis, but not development.
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http://dx.doi.org/10.1080/09537104.2019.1709633 | DOI Listing |
Zool Res
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State Key Laboratory of Estuarine and Coastal Research, School of Life Sciences, East China Normal University, Shanghai 200241, China. E-mail:
Mammalian T-cell responses require synergism between the first signal and co-stimulatory signal. However, whether and how dual signaling regulates the T-cell response in early vertebrates remains unknown. In the present study, we discovered that the Nile tilapia ( ) encodes key components of the LAT signalosome, namely, LAT, ITK, GRB2, VAV1, SLP-76, GADS, and PLC-γ1.
View Article and Find Full Text PDFFront Immunol
April 2023
Centre d'Immunologie de Marseille-Luminy, Aix Marseille Université, INSERM, CNRS, Marseille, France.
The propagation and diversification of signals downstream of the T cell receptor (TCR) involve several adaptor proteins that control the assembly of multimolecular signaling complexes (signalosomes). The global characterization of changes in protein-protein interactions (PPI) following genetic perturbations is critical to understand the resulting phenotypes. Here, by combining genome editing techniques in T cells and interactomics studies based on affinity purification coupled to mass spectrometry (AP-MS) analysis, we determined and quantified the molecular reorganization of the SLP76 interactome resulting from the ablation of each of the three GRB2-family adaptors.
View Article and Find Full Text PDFJ Immunol
May 2021
Department of Immunology, Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel
Mol Immunol
November 2020
Laboratory of Molecular Immunology and Immunotherapy, Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI, United States; Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, United States; Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, United States; Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI, United States. Electronic address:
Effector lymphocytes, including NK and T cells, express FasL. Expression of Fas, the receptor for FasL in tumor cells, renders them susceptible to NK and T cell-mediated killing. The functional relevance of FasL in initiating death signals in tumor cells is well-characterized.
View Article and Find Full Text PDFPlatelets
August 2020
Institute of Experimental Biomedicine I, University Hospital Würzburg and Rudolf Virchow Center, University of Würzburg, Würzburg, Germany.
Platelets are essential for normal hemostasis; however, pathological conditions can also trigger unwanted platelet activation precipitating thrombosis and ischemic damage of vital organs such as the heart or brain. (GP)VI- and (CLEC-2)-mediated (hem) (ITAM) signaling represents a major pathway for platelet activation. The two members of the (Grb2) family of adapter proteins expressed in platelets - Grb2 and (Gads) - are part of the hem(ITAM) signaling cascade by forming an adapter protein complex with (LAT).
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