Abstract
P130CAS/BCAR1 belongs to the CAS family of adaptor proteins, with important regulatory roles in cell migration, cell cycle control, and apoptosis. Previously, we and others showed that P130CAS mediates VEGF-A and PDGF signalling in vitro, but its cardiovascular function in vivo remains relatively unexplored. We characterise here a novel deletion model of P130CAS in zebrafish. Using in vivo microscopy and transgenic vascular reporters, we observed that while bcar1−/− zebrafish showed no arterial angiogenic or heart defects during development, they strikingly failed to form the caudal vein plexus (CVP). Endothelial cells (ECs) within the CVP of bcar1−/− embryos produced fewer filopodial structures and did not detach efficiently from neighbouring cells, resulting in a significant reduction in ventral extension and overall CVP area. Mechanistically, we show that P130Cas mediates Bmp2b-induced ectopic angiogenic sprouting of ECs in the developing embryo and provide pharmacological evidence for a role of Src family kinases in CVP development.
Highlights
P130CAS/BCAR1 belongs to the CAS family of adaptor proteins, with important regulatory roles in cell migration, cell cycle control, and apoptosis
Genetic loss of arterial vs venous specification leads to arteriovenous malformations including A-V shunts that are characteristic of congenital arteriopathies such as hereditary haemorrhagic telangiectasia[2,4,5]
Our group and others have shown that phosphorylation of P130CAS as a result of integrin-mediated adhesion, receptor tyrosine kinase or G-coupled receptor activity, hypoxia, mechanical stretching, or chemokine receptor activation enables different multi-protein complexes which impart downstream signalling, e.g., through FAK, CRK, DOCK180, 14-3-3, SRC, DOK1, ABL, RAP1, IQGAP1 or ERK, controlling cell attachment, migration, cell cycle progression, and cell survival s ignalling[11,12,13]
Summary
P130CAS/BCAR1 belongs to the CAS family of adaptor proteins, with important regulatory roles in cell migration, cell cycle control, and apoptosis. Bmp2-Bmpr[2] signalling was shown to regulate venous cell migration in the caudal vein plexus of the developing zebrafish e mbryo[9].
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