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.