University of Leicester
JCAD complete final accepted paper.pdf (147.4 MB)

JCAD Gene at the 10p11 Coronary Artery Disease Locus Regulates Hippo Signaling in Endothelial Cells.

Download (147.4 MB)
journal contribution
posted on 2018-09-20, 11:01 authored by Peter D. Jones, Michael A. Kaiser, Maryam Ghaderi Najafabadi, Simon Koplev, Yuqi Zhao, Gillian Douglas, Theodosios Kyriakou, Sarah Andrews, Rathinasabapathy Rajmohan, Hugh Watkins, Keith M. Channon, Shu Ye, Xia Yang, Johan L. M. Björkegren, Nilesh J. Samani, Tom R. Webb
OBJECTIVE: A large number of genetic loci have been associated with risk of coronary artery disease (CAD) through genome-wide association studies, however, for most loci the underlying biological mechanism is unknown. Determining the molecular pathways and cellular processes affected by these loci will provide new insights into CAD pathophysiology and may lead to new therapies. The CAD-associated variants at 10p11.23 fall in JCAD, which encodes an endothelial junction protein, however, its molecular function in endothelial cells is not known. In this study, we characterize the molecular role of JCAD (junctional protein associated with CAD) in endothelial cells. APPROACH AND RESULTS: We show that JCAD knockdown in endothelial cells affects key phenotypes related to atherosclerosis including proliferation, migration, apoptosis, tube formation, and monocyte binding. We demonstrate that JCAD interacts with LATS2 (large tumor suppressor kinase 2) and negatively regulates Hippo signaling leading to increased activity of YAP (yes-associated protein), the transcriptional effector of the pathway. We also show by double siRNA knockdown that the phenotypes caused by JCAD knockdown require LATS2 and that JCAD is involved in transmission of RhoA-mediated signals into the Hippo pathway. In human tissues, we find that the CAD-associated lead variant, rs2487928, is associated with expression of JCAD in arteries, including atherosclerotic arteries. Gene co-expression analyses across disease-relevant tissues corroborate our phenotypic findings and support the link between JCAD and Hippo signaling. CONCLUSIONS: Our results show that JCAD negatively regulates Hippo signaling in endothelial cells and we suggest that JCAD contributes to atherosclerosis by mediating YAP activity and contributing to endothelial dysfunction.


This study was supported by a Transatlantic Networks of Excellence Award (12CVD02) from The Leducq Foundation. The research leading to these results has received funding from the European Union Seventh Framework Programme FP7/2007-2013 under grant agreement number HEALTH-F2-2013-601456. H. Watkins, K.M. Channon, N.J. Samani, and T.R. Webb are funded by the British Heart Foundation. K.M. Channon, H. Watkins, and N.J. Samani are UK National Institute for Health Research Senior Investigators. Study was supported by British Heart Foundation grant PG/15/35/31403 to K.M. Channon. Y. Zhao and X. Yang are partially supported by the American Heart Association. The DNA genotyping and RNA sequencing in STARNET of which J.L.M. Björkegren is P.I. were in part performed by the SNP&SEQ technology platform at Science for Life, the National Genomics Infrastructure in Uppsala and Stockholm supported by Swedish Research Council (VR-RF1), Knut and Alice Wallenberg Foundation, and UPPMAX. STARNET has also been supported in part through the computational resources and staff expertise provided by Scientific Computing at the Icahn School of Medicine at Mount Sinai.



Arteriosclerosis, Thrombosis, and Vascular Biology, 2018, 38(8), pp. 1711–1722

Author affiliation

/Organisation/COLLEGE OF LIFE SCIENCES/School of Medicine/Department of Cardiovascular Sciences


  • AM (Accepted Manuscript)

Published in



American Heart Association, Lippincott, Williams & Wilkins





Acceptance date


Copyright date


Available date


Publisher version


The file associated with this record is under embargo until 6 months after publication, in accordance with the publisher's self-archiving policy. The full text may be available through the publisher links provided above.



Usage metrics

    University of Leicester Publications


    No categories selected


    Ref. manager