Finally, increased intracellular Ca2+ leads to the activation of the cytosolic EF-hand domain containing Ca2+ sensor CalDAG-GEFI that links Ca2+ mobilization to signaling pathways regulating thromboxane A2 generation, integrin activation and granule release, thereby promoting platelet spreading, clot retraction, coagulant activity, and platelet aggregation. EF-hand domain containing 2 belongs to the EF-hand superfamily of Ca2+binding proteins, consisting of an N-terminal region of low complexity with an alanine stretch, a functional SH3 binding motif, two functional EF hands and a C-terminal coiled-coil domain, the latter capable of mediating self-oligomerization in a Ca2+dependent manner. Constitutive EFhd2-deficient mice revealed a function of this cytoskeletal adaptor protein in the negative regulation of germinal center-dependent humoral immunity. Besides B cells and other hematopoietic cells, EFhd2 is predominantly expressed in the brain and has been associated with tau-mediated neurodegeneration. In addition, EFhd2 negatively regulates axonal transport in hippocampal neurons by inhibiting kinesin mediated microtubule gliding. In natural killer -like cells, EFhd2 was found in the cytoskeleton fraction together with actin and actin-binding proteins such as a-actinin and filamin and it was shown that EFhd2 directly binds to F-actin thereby modulating F-actin bundling and cell spreading in a Ca2+-dependent manner. In line with this, EFhd2 co-localizes with F-actin and regulates actin remodeling in a human mast cell line and modulates Haloperidol lamellipodial dynamics by regulating the accessibility of F-actin to cofilin in melanoma cells. A study characterizing sepsisinduced changes in the MK�Cplatelet Amikacin hydrate transcriptional axis revealed that EFhd2 mRNA was highly up-regulated in mice after induction of sepsis by the cecal ligation and puncture model. Furthermore, a proteomic approach identified a minor upregulation of EFhd2 expression in rat and human platelets upon stimulation with thrombin. However, due to the lack of an appropriate animal model, the role of EFhd2 in platelet function has remained elusive.