erent 25036716 receptors. Binding of the BMP ligands to the type I receptor leads to phosphorylation by the constitutively active type II receptor. The receptor complex phosphorylates Smad-1/ 5, which then activates the transcription of downstream target genes. During embryonic development, BMPs regulates cell fate 
2449244 decisions, cell survival, and vasculogenesis, processes that are also common in carcinogenesis. In fact, BMP-2 is overexpressed in 98% of NSCLC and other carcinomas. BMP expression inversely correlates with survival and high expression is associated with metastatic spread. BMP-2 enhances tumor angiogenesis and stimulates tumor invasion. Ectopic expression of BMP-2 in A549 lung cancer cells greatly enhanced metastatic Vonoprazan site growth in a murine model of lung cancer following tail vein injection. Studies using recombinant BMP proteins or knockdown of a single BMP receptor have suggested that BMP signaling in cancer cells does not promote cell growth and may even act as a tumor suppressor. The effects of inhibiting multiple BMP receptors on cell growth and survival in cancer cells has not been examined. Therefore, the biological significance of a basally active BMP signaling cascade in cancer cells is not known. 1 BMP Receptor Antagonists Inhibit Cell Growth During development the inhibitors of DNA binding/differentiation are direct mediators of BMP signaling. There are 4 Id family members. BMP response elements on the Id1, Id2, and Id3 promoters are activated by Smad 1/5/8. The Id proteins inhibit lineage commitment by binding and sequestering basic HLH transcription factors. Id family members have been implicated in oncogenic transformation in several types of cancers . Id1 has been reported to regulate invasion, proliferation, survival, and the metastatic spread of cancer cells. Id family members are frequently expressed in non-small cell lung carcinomas and over-expression is associated with a shorter disease free survival. These studies suggest that targeting signaling pathways, which regulate the expression of Id family members may have important therapeutic implications. Although recombinant BMP2 proteins induce a transient increase in the expression of Id1 in lung cancer cells, the role of the BMP signaling cascade in regulating the basal expression levels of the Id family members in cancer cells has not been elucidated. The aim of this study was to determine in lung cancer cell lines, which have not been stimulated with a recombinant BMP protein, whether cells have a basally active BMP signaling and determine its effect on cell growth, survival, and expression of Id family members. Selective BMP type I receptor antagonists and siRNA targeting the BMP type I receptors reveals that basally active BMP signaling in lung cancer cell lines is growth promoting and an important regulator of the expression of Id family members. BMP signaling is mediated through more than one type I BMP receptor. DMH2 caused the greatest inhibition of BMP signaling and induced the greatest reduction of cell growth and expression of Id family members. Multiple BMP Type I Receptors Mediate Signaling Next, we assessed whether a specific BMP type I receptor mediates basally active BMP signaling in lung cancer cell lines. By quantitative RT-PCR, the expression of BMP type I receptors was examined. Alk1 was not expressed in either A549 or H1299 cells. As expected, alk1 was expressed in human endothelial cells. Alk2, alk3, and alk6 mRNA are expressed in A549 and H1299 c