Molecular Characteristics of Pancreatic Ductal Adenocarcinoma

Figure 7

Left Notch signaling. Upon Notch ligand binding, ADAM performs the first cleavage quickly followed by the second cleavage performed by γ-secretase. This second cleavage releases the Notch intracellular domain (NICD) into the cellular lumen. NICD transports to the nucleus where it interacts with a transcription domain resulting in transcription of the Notch target genes. Right Hedgehog signaling. In normal pancreatic cells, Hedgehog signaling is repressed; the patched (PTCH) receptor represses the smoothened (SMO) receptor. Intracellularly, the hedgehog inhibitor suppressor of fused (SUFU) binds the GLI family zink finger transcription factors GLI2/3 thereby inducing proteasomal cleavage resulting in repressor forms of GLI2/3. When one of the Hedgehog ligands attaches to Patched, this abrogates the inhibition on Smoothened. Smoothened inhibits proteasomal cleavage of GLI2/3 and thereby facilitates transcriptional activity.