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5. The Secreted Tyrosine Kinase Vlk Is Essential for Normal Platelet Activation and Thrombus Formation

Author

Revollo, Leila, primary, Merrill-Skoloff, Glenn, additional, De Ceunynck, Karen, additional, Dilks, James, additional, Bordoli, Mattia, additional, Peters, Christian, additional, Noetzli, Leila, additional, Ionescu, Andreia, additional, Rosen, Vicki, additional, Italiano, Joseph E., additional, Whitman, Malcolm, additional, and Flaumenhaft, Robert, additional

Published
2020
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6. Loss of Vlk in Prx1+ Cells Delays the Initial Steps of Endochondral Bone Formation and Fracture Repair in the Limb.

Author

Maridas, David E, Gamer, Laura, Moore, Emily R, Doedens, Annemiek M, Yu, Yunqing, Ionescu, Andreia, Revollo, Leila, Whitman, Malcolm, and Rosen, Vicki

Abstract

Vertebrate lonesome kinase (Vlk) is a secreted tyrosine kinase important for normal skeletogenesis during embryonic development. Vlk null mice (Vlk−/−) are born with severe craniofacial and limb skeletal defects and die shortly after birth. We used a conditional deletion model to remove Vlk in limb bud mesenchyme (Vlk‐Prx1 cKO) to assess the specific requirement for Vlk expression by skeletal progenitor cells during endochondral ossification, and an inducible global deletion model (Vlk‐Ubq iKO) to address the role of Vlk during fracture repair. Deletion of Vlk with Prx1‐Cre recapitulated the limb skeletal phenotype of the Vlk−/− mice and enabled us to study the postnatal skeleton as Vlk‐Prx1 cKO mice survived to adulthood. In Vlk‐Prx1 cKO adult mice, limbs remained shorter with decreased trabecular and cortical bone volumes. Both Vlk‐Prx1 cKO and Vlk‐Ubq iKO mice had a delayed fracture repair response but eventually formed bridging calluses. Furthermore, levels of phosphorylated osteopontin (OPN) were decreased in tibias of Vlk‐Ubq iKO, establishing OPN as a Vlk substrate in bone. In summary, our data indicate that Vlk produced by skeletal progenitor cells influences the timing and extent of chondrogenesis during endochondral bone formation and fracture repair. © 2022 American Society for Bone and Mineral Research (ASBMR). [ABSTRACT FROM AUTHOR]

Published
2022
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15. The secreted tyrosine kinase VLK is essential for normal platelet activation and thrombus formation

Author

Revollo, Leila, Merrill-Skoloff, Glenn, De Ceunynck, Karen, Dilks, James R., Guo, Shihui, Bordoli, Mattia, Peters, Christian G., Noetzli, Leila, Ionescu, Andreia, Rosen, Vicki, Italiano, Joseph E., Whitman, Malcolm, and Flaumenhaft, Robert

Abstract

Tyrosine phosphorylation of extracellular proteins is observed in cell cultures and in vivo, but little is known about the functional roles of tyrosine phosphorylation of extracellular proteins. Vertebrate Lonesome Kinase (VLK) is a broadly expressed secretory pathway tyrosine kinase present in platelet α-granules. It is released from platelets upon activation and phosphorylates substrates extracellularly. Its role in platelet function, however, has not been previously studied. In human platelets, we identified phosphorylated tyrosines mapped to luminal or extracellular domains of transmembrane and secreted proteins implicated in the regulation of platelet activation. To determine the role of VLK in extracellular tyrosine phosphorylation and platelet function, we generated mice with a megakaryocyte/platelet-specific deficiency of VLK. Platelets from these mice are normal in abundance and morphology, but have significant changes in function both in vitro and in vivo. Resting and thrombin-stimulated VLK-deficient platelets demonstrate a significant decrease of several tyrosine phosphobands. Functional testing of VLK-deficient platelets shows decreased PAR4- and collagen-mediated platelet aggregation, but normal responses to ADP. Dense granule and α-granule release are reduced in these platelets. Furthermore, VLK-deficient platelets exhibit decreased PAR4-mediated Akt (S473) and Erk1/2(T202/Y204) phosphorylation, indicating altered proximal signaling. In vivo, mice lacking VLK in megakaryocytes/platelets demonstrate strongly reduced platelet accumulation and fibrin formation following laser-injury of cremaster arterioles compared to controls, but normal bleeding times. These studies demonstrate that the secretory pathway tyrosine kinase VLK is critical for stimulus-dependent platelet activation and thrombus formation, providing the first evidence that a secreted protein kinase is required for normal platelet function.

Published
2021
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