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In vitro phosphorylation of von Willebrand factor by FAM20c enhances its ability to support platelet adhesion
Author(s): ,
Qi Da
Affiliations:
Department of Medicine, Baylor College of Medicine, Houston, USA. Center for Translational Research on Inflammatory Diseases (CTRID), Michael E. DeBakey Veterans Affairs Medical Center (MEDVAMC), Houston, USA
,
Hyojeong Han
Affiliations:
Center for Translational Research on Inflammatory Diseases (CTRID), Michael E. DeBakey Veterans Affairs Medical Center (MEDVAMC), Houston, USA. Department of Pediatrics, Baylor College of Medicine, Houston, USA
,
Christian Valladolid
Affiliations:
Department of Medicine, Baylor College of Medicine, Houston, USA. Center for Translational Research on Inflammatory Diseases (CTRID), Michael E. DeBakey Veterans Affairs Medical Center (MEDVAMC), Houston, USA. Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, USA
,
María Fernández
Affiliations:
Department of Medicine, Baylor College of Medicine, Houston, USA. Center for Translational Research on Inflammatory Diseases (CTRID), Michael E. DeBakey Veterans Affairs Medical Center (MEDVAMC), Houston, USA
,
Tanvir Khatlani
Affiliations:
Department of Medicine, Baylor College of Medicine, Houston, USA. Center for Translational Research on Inflammatory Diseases (CTRID), Michael E. DeBakey Veterans Affairs Medical Center (MEDVAMC), Houston, USA
,
Subhashree Pradhan
Affiliations:
Department of Medicine, Baylor College of Medicine, Houston, USA. Center for Translational Research on Inflammatory Diseases (CTRID), Michael E. DeBakey Veterans Affairs Medical Center (MEDVAMC), Houston, USA
,
Jennifer Nolasco
Affiliations:
Department of Medicine, Baylor College of Medicine, Houston, USA. Center for Translational Research on Inflammatory Diseases (CTRID), Michael E. DeBakey Veterans Affairs Medical Center (MEDVAMC), Houston, USA
,
Risë K. Matsunami
Affiliations:
Houston Methodist Hospital Research Institute, Houston, USA
,
David A. Engler
Affiliations:
Houston Methodist Hospital Research Institute, Houston, USA
,
Miguel A. Cruz
Affiliations:
Department of Medicine, Baylor College of Medicine, Houston, USA. Center for Translational Research on Inflammatory Diseases (CTRID), Michael E. DeBakey Veterans Affairs Medical Center (MEDVAMC), Houston, USA. Department of Pediatrics, Baylor College of Medicine, Houston, USA. Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, USA
Correspondence: K. Vinod Vijayan/Miguel A. Cruz, Cardiovascular Research Section, Baylor College of Medicine and MEDVAMC, Rm. 146, Bldg. 109, 2002 Holcombe Blvd, Houston, TX 77030, USA|Tel.: +1 713 770 1822/713 794 7775|E‐mails: /vvijayan@bcm.edu
K. Vinod Vijayan
Affiliations:
Department of Medicine, Baylor College of Medicine, Houston, USA. Center for Translational Research on Inflammatory Diseases (CTRID), Michael E. DeBakey Veterans Affairs Medical Center (MEDVAMC), Houston, USA. Department of Pediatrics, Baylor College of Medicine, Houston, USA. Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, USA
Correspondence: K. Vinod Vijayan/Miguel A. Cruz, Cardiovascular Research Section, Baylor College of Medicine and MEDVAMC, Rm. 146, Bldg. 109, 2002 Holcombe Blvd, Houston, TX 77030, USA|Tel.: +1 713 770 1822/713 794 7775|E‐mails: /vvijayan@bcm.edu
ISTH Academy. Vinod Vijayan K.
May 31, 2019; 273616
K. Vinod Vijayan
K.  Vinod Vijayan
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Journal Abstract
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Background
von Willebrand factor (VWF) mediates platelet adhesion and contributes to hemostasis at sites of vascular injury as well as to arterial thrombosis. The A1A2A3 domains of VWF contain important sites that differentially participate in supporting platelet adhesion. FAM20c (family with sequence similarity 20, member C) has emerged as a serine/threonine kinase, which phosphorylates extracellular proteins containing the S‐X‐E/pS motifs that are also found within the VWF A domains. This is of interest because we and others have shown that structural modifications within these A domains influence the ability of VWF to support platelet adhesion.
Objective
We assessed if VWF A domains can be phosphorylated and the functional consequence of phosphorylated VWF.
Results
Here, we show that FAM20c phosphorylated purified plasma VWF, VWF A1A2A3 protein, isolated A2 domain, but not A1 and A3 domain proteins, in vitro. FAM20c phosphorylated the isolated A2 domain at S1517 and S1613 within the S‐X‐E recognition motif, with S1613 being the major phosphorylation site. Mass spectrometry analysis of purified plasma VWF from healthy donors revealed several phosphorylation sites, including the S1613 in the A2 domain. VWF A1A2A3 domain protein phosphorylated at S1613 promoted stable platelet adhesion and microthrombi at high shear stress. Lastly, under high shear stress VWF treated with FAM20c and ATP robustly supported platelet adhesion, compared to VWF treated with FAM20c in the absence of ATP.
Conclusion
These outcomes indicate that VWF can be phosphorylated by FAM20c in vitro, and this novel post‐translational modification enhances the adhesiveness of VWF to platelets.
Keyword(s)
blood platelets, cell adhesion, phosphorylation, protein kinase, von Willebrand factor
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