Myosin light chain 6 (Myl6) interacts with kindlin-3 and is required to support integrin α_IIbβ₃ activation in...

Kindlin-3 in platelets plays an essential role in supporting integrin α_IIbβ₃ activation, platelet spreading, aggregation, and clot retraction by binding to the integrin β₃ cytoplasmic tail. However, the mechanism by which kindlin-3 mediates the crosstalk between integrin α_IIbβ₃ and myosin in platelets remains unknown.

To examine the role of myosin light chain 6 (Myl6) in supporting integrin α_IIbβ₃ activation in platelets.

Myl6^fl/flPF4-Cre mice with a deficiency of Myl6 in the megakaryocyte lineage were generated, and integrin α_IIbβ₃ activation in Myl6-deficient platelets was analyzed.

We identified a novel kindlin-3 binding protein, Myl6, an essential light chain of myosin in platelets. Myl6^fl/flPF4-Cre mice exhibited significant macrothrombocytopenia resulting from defective proplatelet formation. In the absence of Myl6, integrin α_IIbβ₃ activation in platelets was significantly suppressed, and platelet aggregation was substantially impaired. Interestingly, the deficiency of Myl6 in platelets preferentially affected the binding of a multivalent ligand compared to a monovalent ligand to integrin α_IIbβ₃ upon activation, indicating that Myl6 may contribute to the avidity modulation of integrin α_IIbβ₃ by binding to kindlin-3. Furthermore, blood coagulation ability was impaired in Myl6^fl/flPF4-Cre mice, and consistently, these mice exhibited defects in both hemostatic and thrombotic functions.

In summary, these results suggest that Myl6, as a novel kindlin-3 binding partner, is required to support integrin α_IIbβ₃ activation in platelets, which plays an important role in both hemostasis and thrombosis.