Myosin light chain 6 (Myl6) interacts with kindlin-3 and is required to support integrin α IIb β 3 activation in platelets in mice.

Background: Kindlin-3 in platelets plays an essential role in supporting integrin α _IIb β ₃ activation, platelet spreading, aggregation, and clot retraction by binding to the integrin β ₃ cytoplasmic tail. However, the mechanism by which kindlin-3 mediates the crosstalk between integrin α _IIb β ₃ and myosin in platelets remains unknown.
Objectives: To examine the role of myosin light chain 6 (Myl6) in supporting integrin α _IIb β ₃ activation in platelets.
Methods: Myl6 ^fl/fl PF4-Cre mice with a deficiency of Myl6 in the megakaryocyte lineage were generated, and integrin α _IIb β ₃ activation in Myl6-deficient platelets was analyzed.
Results: We identified a novel kindlin-3 binding protein, Myl6, an essential light chain of myosin in platelets. Myl6 ^fl/fl PF4-Cre mice exhibited significant macrothrombocytopenia resulting from defective proplatelet formation. In the absence of Myl6, integrin α _IIb β ₃ 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 _IIb β ₃ upon activation, indicating that Myl6 may contribute to the avidity modulation of integrin α _IIb β ₃ by binding to kindlin-3. Furthermore, blood coagulation ability was impaired in Myl6 ^fl/fl PF4-Cre mice, and consistently, these mice exhibited defects in both hemostatic and thrombotic functions.
Conclusion: In summary, these results suggest that Myl6, as a novel kindlin-3 binding partner, is required to support integrin α _IIb β ₃ activation in platelets, which plays an important role in both hemostasis and thrombosis.
Competing Interests: Declaration of competing interests The authors declare no competing financial interests.
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