Dedicator of cytokinesis 2 regulates cytoskeletal actin dynamics and is essential for platelet biogenesis and functions.

This article focuses on the role of Dedicator of cytokinesis 2 (DOCK2), a guanine nucleotide exchange factor acting on Rho GTPases, in platelet biogenesis and function. Using DOCK2-deficient (Dock2−/−) mice, the study demonstrates that DOCK2 deficiency causes macrothrombocytopenia characterized by enlarged platelets and reduced platelet count due to impaired proplatelet formation in megakaryocytes. Mechanistically, DOCK2 regulates platelet actin cytoskeleton dynamics by modulating Rac1 activity and GPVI receptor clustering, leading to defective immunoreceptor tyrosine-based activation motif (ITAM) signaling, diminished platelet aggregation, and reduced thrombus formation and thrombo-inflammation in vivo. Pharmacological inhibition of DOCK2 similarly impairs platelet spreading, clot retraction, and thrombus formation, suggesting DOCK2 as a potential therapeutic target for thrombotic and thrombo-inflammatory diseases.