BioProject

Transforming growth factor-b (TGF-b) regulates various aspects of vascular development, yet the signaling mechanisms of TGF-b in the control of angiogenesis remain poorly characterized. More...

Transforming growth factor-b (TGF-b) regulates various aspects of vascular development, yet the signaling mechanisms of TGF-b in the control of angiogenesis remain poorly characterized. Here we show that homeodomain interacting protein kinases, HIPK1 and HIPK2, are transcriptional corepressors that regulate TGF-b-depednent angiogenesis during embryonic development. Loss of HIPK1 and HIPK2 leads to marked up-regulations of several potent angiogenic genes, including Vegf and Mmp10, which result in excessive endothelial proliferation and poor adherens junction formation. This robust phenotype can be recapitulated by siRNA knock down of Hipk1 and Hipk2 in human umbilical vein endothelial cells, as well as in endothelial cell-specific TGF-b type II receptor (TbRII) conditional mutants. The effects of HIPK proteins are mediated through its interaction with MEF2C and HDAC7, and this interaction can be further enhanced by TGF-b and TAK1. Remarkably, TGF-b-TAK1 signaling activates HIPK2 by phosphorylating a highly conserved tyrosine residue Y-361 within the kinase domain. Point mutation in this tyrosine completely eliminates the effect of HIPK2 in the transcriptional suppression of target genes. Together, these results reveal a previously unrecognized role of HIPK proteins in connecting TGF-b signaling pathway with the transcriptional programs for angiogenesis in early embryonic development. Overall design: In this study, a total of 36,000 transcripts and ESTs (a total of 30,000 unique genes) was used to acquire expression profiles among the control, Hipk1-/-, Hipk2-/-, and Hipk1-/-;Hipk2-/- E9.5 embryos. This will allow us unsupervised and successfully to analyze the transcriptomes and finally to reveal the role of HIPK1 and HIPK2 in the signal transduction mechanism downstream of TGF-b and the transcriptional control of angiogenic gene expression during the critical stages of vascular morphogenesis. Less...