TRAF7 is an essential regulator of blood vessel integrity during mouse embryonic and neonatal development
Erdyni N. Tsitsikov,
Khanh P. Phan,
Yufeng Liu,
Alla V. Tsytsykova,
Mike Kinter,
Lauren Selland,
Lori Garman,
Courtney Griffin,
Ian F. Dunn
Affiliations
Erdyni N. Tsitsikov
Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
Khanh P. Phan
Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
Yufeng Liu
Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
Alla V. Tsytsykova
Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
Mike Kinter
Aging & Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA
Lauren Selland
Histology, Immunohistochemistry, Microscopy Core-COBRE Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
Lori Garman
Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
Courtney Griffin
Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA
Ian F. Dunn
Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; Corresponding author
Summary: Targeted deletion of TRAF7 revealed that it is a crucial part of shear stress-responsive MEKK3-MEK5-ERK5 signaling pathway induced in endothelial cells by blood flow. Similar to Mekk3-, Mek5- or Erk5-deficient mice, Traf7-deficient embryos died in utero around midgestation due to impaired endothelium integrity. They displayed significantly lower expression of transcription factor Klf2, an essential regulator of vascular hemodynamic forces downstream of the MEKK3-MEK-ERK5 signaling pathway. In addition, deletion of Traf7 in endothelial cells of postnatal mice was associated with severe cerebral hemorrhage. Here, we show that besides MEKK3 and MEK5, TRAF7 associates with a planar cell polarity protein SCRIB. SCRIB binds with an N-terminal region of TRAF7, while MEKK3 associates with the C-terminal WD40 domain. Downregulation of TRAF7 as well as SCRIB inhibited fluid shear stress-induced phosphorylation of ERK5 in cultured endothelial cells. These findings suggest that TRAF7 and SCRIB may comprise an upstream part of the MEKK3-MEK5-ERK5 signaling pathway.
