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The novel protein ADTRP, which we first reported and described in 2011, is androgen-inducible and regulates the expression and activity of Tissue Factor Pathway Inhibitor, the key inhibitor of the Tissue Factor-dependent pathway of coagulation on endothelial cells. ADTRP also hydrolyses fatty acid esters of hydroxy-fatty acids, which have anti-diabetic and anti-inflammatory properties and can regulate metabolic disorders.
Source link: https://doi.org/10.3390/ijms22094451
C6ORF105 expression co-regulates with tissue factor pathway inhibitor in human endothelial cells, causing a cellular gene expression inhibitor, hence we referred to this protein as "androgen-dependent TFPI-regulating protein". We discovered ADTRP as a negative regulator of canonical Wnt signaling in human cells using in vitro cell-based TOP-Flash reporter Assay we found it in human cells. The expression of ADTRP in HEK293T cells resulted in decreased phosphorylation of Wnt co-receptor LRP6, implying that ADTRP can influence this important membrane-located event of Wnt signaling. These results, taken together, show that ADTRP's Wnt signaling inhibitory function exists at the plasma membrane level. The mutagenesis of the proposed palmitoyl-mediated anchoring of Wnt inhibity results of ADTRP necessitate palmitoyl-mediated anchoring, emphasizing the importance of determining ADTRP's optimal membrane location for Wnt pathway inhibition. Also, the downing of adtrp in a Wnt reporter zebrafish screamed at increased frequency of ectopic Wnt signaling. Plasma TFPI antigen deficiency decreased by 2% in ADTRP by 2-times. TIPI antigen and anticoagulant activity in lung extracts and isolated lung EC was also reduced, which supports our previous in vitro results. We aslo experienced increased tail bleeding time and blood volume loss, which could be attributed to increased dilation of the tail vein. Similarly, skin fibroblasts and lung EC isolated from Adtrp-/- mice increased expression of Wnt target genes, which indicates constitutive activation of canonical Wnt signaling. For the first time, we used genetic animal models and cell culture techniques to demonstrate that the novel protein ADTRP plays a key role in vascular formation and function in vascular formation and function.
Source link: https://doi.org/10.1182/blood.v128.22.556.556
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