Figure 6

PTK7 signaling. The pathways and the key proteins are predicted based on the results of our genome-wide transcriptional and protein phosphorylation profiling. Our data suggest that the stabilized full-length membrane PTK7 up-regulates the Akt and c-Jun pathways, and down-regulates the p53 pathways leading to the cell survival signaling. Full-length PTK7 also suppresses ERK and CREB-mediated gene expression and cell motility. The proteolysis of PTK7 ectodomain (Ig1-Ig7) by MT1-MMP and ADAMs generates the soluble sPTK7 form. The subsequent cleavage of the C-terminal membrane PTK7 fragment by γ-secretase releases the intracellular domain (cPTK7). The soluble sPTK7 species binds the full-length membrane PTK7 and activates the RhoA [21] and p38a pathways, which regulate the actin cytoskeleton and the expression of the migratory genes, including IL1B. The intracellular PTK7 domain fragment, cPTK7, enters the cell nucleus and induces the RAS/p90RSK/CREB signaling resulting in the CREB and ATF1 phosphorylation at Ser133 and Ser63, respectively, and the expression of the pro-migratory genes, including cadherin-11 (CDH11). We hypothesize that the ratio of the full-length membrane PTK7 to the N-terminal and the C-terminal PTK7 proteolytic fragments acts as a switch, which establishes the downstream signaling pathways that control cell survival and motility.