Critical redundant functions of the adapters Grb2 and Gads in platelet (hem)ITAM signaling in mice

Voegtle T, Baig AA, Volz J, Duchow TB, Pleines I, Duetting S, Nitschke L, Watson SP, Nieswandt B (2020)

Publication Type: Journal article

Publication year: 2020

Journal

Platelets Informa Healthcare

DOI: 10.1080/09537104.2019.1709633

Abstract

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. Glycoprotein (GP)VI- and C-type lectin-like receptor 2 (CLEC-2)-mediated (hem)immunoreceptor tyrosine-based activation motif (ITAM) signaling represents a major pathway for platelet activation. The two members of the Growth-factor receptor-bound protein 2 (Grb2) family of adapter proteins expressed in platelets - Grb2 and Grb2-related adapter protein downstream of Shc (Gads) - are part of the hem(ITAM) signaling cascade by forming an adapter protein complex with linker for activation of T cells (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 double knockout (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.

Authors with CRIS profile

Lars Nitschke Professur für Genetik

Involved external institutions

Julius-Maximilians-Universität Würzburg DE Germany (DE) University of Birmingham GB United Kingdom (GB)

How to cite

APA:

Voegtle, T., Baig, A.A., Volz, J., Duchow, T.B., Pleines, I., Duetting, S.,... Nieswandt, B. (2020). Critical redundant functions of the adapters Grb2 and Gads in platelet (hem)ITAM signaling in mice. Platelets. https://doi.org/10.1080/09537104.2019.1709633

MLA:

Voegtle, Timo, et al. "Critical redundant functions of the adapters Grb2 and Gads in platelet (hem)ITAM signaling in mice." Platelets (2020).

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