TY - JOUR
T1 - Structural and cellular mechanisms of peptidyl-prolyl isomerase Pin1-mediated enhancement of tissue factor gene expression, protein half-life, and pro-coagulant activity
AU - Kurakula, Kondababu
AU - Koenis, Duco S.
AU - Herzik, Mark A.
AU - Liu, Yanyun
AU - Craft, John W.
AU - van Loenen, Pieter B.
AU - Vos, Mariska
AU - Tran, M. Khang
AU - Versteeg, Henri H.
AU - Goumans, Marie José T.H.
AU - Ruf, Wolfram
AU - de Vries, Carlie J.M.
AU - Şen, Mehmet
N1 - Funding Information: This work was supported by the research program of the BioMedical Materials institute, co-funded by the Dutch Ministry of Economic Affairs as a part of Project P1.02 NEXTREAM. This work was also supported by the Rembrandt Institute for Cardiovascular Research (RICS-grant 2013), the Netherlands CardioVascular Research Initiative (CVON: 2012-08), and the National Institute of Health (grants HL-60742 and P01-HL16411). Funding Information: This work was supported by the research program of the BioMedical Materials institute, co-funded by the Dutch Ministry of Economic Affairs as a part of Project P1.02 NEXTREAM. This work was also supported by the Rembrandt Institute for Cardiovascular Research (RICS-grant 2013), the Netherlands CardioVascular Research Initiative (CVON: 2012-08), and the National Institute of Health (grants HL-60742 and P01-HL16411). Acknowledgments We would like to thank Dr. Youlin Xia and the UH NMR facility-DOR for NMR data acquisition, CACDS for the structure calculations, and Amr Elnashai, Amy Sater, and Glen Legge for their support of this research. Publisher Copyright: © 2018 Ferrata Storti Foundation.
PY - 2018/6/3
Y1 - 2018/6/3
N2 - Tissue Factor is a cell-surface glycoprotein expressed in various cells of the vasculature and is the principal regulator of the blood coagulation cascade and hemostasis. Notably, aberrant expression of Tissue Factor is associated with cardiovascular pathologies such as atherosclerosis and thrombosis. Here, we sought to identify factors that regulate Tissue Factor gene expression and activity. Tissue Factor gene expression is regulated by various transcription factors, including activating protein-1 and nuclear factor-κ B. The peptidyl-prolyl isomerase Pin1 is known to modulate the activity of these two transcription factors, and we now show that Pin1 augments Tissue Factor gene expression in both vascular smooth muscle cells and activated endothelial cells via activating protein-1 and nuclear factor-κ B signaling. Furthermore, the cytoplasmic domain of Tissue Factor contains a well-conserved phospho-Ser258-Pro259 amino-acid motif recognized by Pin1. Using co-immunoprecipi-tation and solution nuclear magnetic resonance spectroscopy, we show that the WW-domain of Pin1 directly binds the cytoplasmic domain of Tissue Factor. This interaction occurs via the phospho-Ser258-Pro259 sequence in the Tissue Factor cytoplasmic domain and results in increased protein half-life and pro-coagulant activity. Taken together, our results establish Pin1 as an upstream regulator of Tissue Factor-mediated coagulation, thereby opening up new avenues for research into the use of specific Pin1 inhibitors for the treatment of diseases characterized by pathological coagulation, such as thrombosis and atherosclerosis.
AB - Tissue Factor is a cell-surface glycoprotein expressed in various cells of the vasculature and is the principal regulator of the blood coagulation cascade and hemostasis. Notably, aberrant expression of Tissue Factor is associated with cardiovascular pathologies such as atherosclerosis and thrombosis. Here, we sought to identify factors that regulate Tissue Factor gene expression and activity. Tissue Factor gene expression is regulated by various transcription factors, including activating protein-1 and nuclear factor-κ B. The peptidyl-prolyl isomerase Pin1 is known to modulate the activity of these two transcription factors, and we now show that Pin1 augments Tissue Factor gene expression in both vascular smooth muscle cells and activated endothelial cells via activating protein-1 and nuclear factor-κ B signaling. Furthermore, the cytoplasmic domain of Tissue Factor contains a well-conserved phospho-Ser258-Pro259 amino-acid motif recognized by Pin1. Using co-immunoprecipi-tation and solution nuclear magnetic resonance spectroscopy, we show that the WW-domain of Pin1 directly binds the cytoplasmic domain of Tissue Factor. This interaction occurs via the phospho-Ser258-Pro259 sequence in the Tissue Factor cytoplasmic domain and results in increased protein half-life and pro-coagulant activity. Taken together, our results establish Pin1 as an upstream regulator of Tissue Factor-mediated coagulation, thereby opening up new avenues for research into the use of specific Pin1 inhibitors for the treatment of diseases characterized by pathological coagulation, such as thrombosis and atherosclerosis.
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UR - https://www.ncbi.nlm.nih.gov/pubmed/29545340
U2 - https://doi.org/10.3324/haematol.2017.183087
DO - https://doi.org/10.3324/haematol.2017.183087
M3 - Article
C2 - 29545340
SN - 0390-6078
VL - 103
SP - 1073
EP - 1082
JO - Haematologica
JF - Haematologica
IS - 6
ER -