The observation that IN/IGF1/IRS1/RAS/RAF/MAPK/ERK, IN/IGF1/IRS1/PI3K/AKT and WNT/β-catenin pathways upregulate ASPH at the transcriptional level and crosstalk with each other [31-33] links these growth factor signaling cascades that are commonly upregulated in PC [34-45] to Notch activation through ASPH. The gene discussed is IRS1; the disease is pachyonychia congenita.