Abstract
ABSTRACTAngiogenesis, the formation of new blood vessels from the pre-existing vasculature, is related to numerous pathophysiological events. We previously reported that a RING ubiquitin ligase complex scaffold protein, cullin-3 (CUL3), and one of its adaptor proteins, BAZF, regulated angiogenesis in the mouse retina by suppressing Notch signaling. However, the degree of inhibition of angiogenesis was made greater by CUL3 depletion than by BAZF depletion, suggesting other roles of CUL3 in angiogenesis besides the regulation of Notch signaling. In the present study, we found that CUL3 was critical for the cell surface level of integrin β1, an essential cell adhesion molecule for angiogenesis in HUVECs. By siRNA screening of 175 BTBPs, a family of adaptor proteins for CUL3, we found that ANKFY1/Rabankyrin-5, an early endosomal BTBP, was also critical for localization of surface integrin β1 and angiogenesis. CUL3 interacted with ANKFY1 and was required for the early endosomal localization of ANKFY1. These data suggest that CUL3/ANKFY1 regulates endosomal membrane traffic of integrin β1. Our results highlight the multiple roles of CUL3 in angiogenesis, which are mediated through distinct CUL3-adaptor proteins.
Highlights
Angiogenesis is essential to deliver oxygen and nutrients and dispose waste in the body for survival, but is related to a variety of diseases (Carmeliet and Jain, 2011)
We further showed that ANKFY1 was a CUL3-associated BTBP that was essential for the endosomal membrane traffic of integrin β1, cell spreading on the basement membrane (BM), and angiogenesis in vitro
CUL3 is required for localization of integrin β1 on the surface of endothelial cells Given accumulating evidence that CUL3 functions in membrane trafficking (Gschweitl et al, 2016; Jin et al, 2012; Yuan et al, 2014), we examined whether CUL3 regulates the plasma membrane (PM) localization of integrin β1, an essential angiogenic factor in endothelial cells (Carlson et al, 2008; Hongu et al, 2015; Lei et al, 2008; Tanjore et al, 2008; Yamamoto et al, 2015; Zovein et al, 2010)
Summary
Angiogenesis (the process of new blood vessel growth) is essential to deliver oxygen and nutrients and dispose waste in the body for survival, but is related to a variety of diseases (e.g., stroke, neurodegeneration, cancer, inflammatory disorders, hypertension, blinding eye diseases) (Carmeliet and Jain, 2011). A CUL3/BAZF complex polyubiquitinated a nuclear protein CBF1 for its proteasomal degradation (Ohnuki et al, 2012), a protein that forms a complex with the intracellular domain of Notch (NICD) at the specific DNA sites to induce anti-angiogenic genes that include HEY1 and HEY2 (Fischer et al, 2004). These results suggested that CUL3/BAZF function in the nucleus to regulate the transcription of certain genes for angiogenesis.
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