Cancer Stem Cells: From an Insight into the Basics to Recent Advances and Therapeutic Targeting

Figure 5

Signaling pathways involved in cancer stem cells. (a) The JAK/STAT pathway (extreme left): JAKs get activated when ligands bind to its receptor; JAK1 and JAK2 auto and transphosphorylate each other and also phosphorylate the tyrosine residues present in the cytoplasmic domain of the receptor. STATs upon phosphorylation by JAKs form dimers and are then translocated into the nucleus to initiate the transcription of the targeted genes. (b) The Hedgehog pathway (left): Hh, when secreted from the other cells, binds to PTCH and allows the activation (indicated by black arrows) of SMO. SMO protein complex secretes Gli1/2 and translocates it into the nucleus, leading to the transcription of Hh-associated genes (depicted by purple arrows). (c) The Notch pathway (right): the binding of the delta ligand to the other cell; two different enzymes responsible for two different cleavages are ADAM10 or TACE and a metalloprotease that catalyzes the S2 cleavage and hence producing a substrate for S3 cleavage via the γ-secretase complex. Due to proteolysis, it mediates the release of NCID, which upon translocation into the nucleus starts interacting with the DNA-binding CSL protein and MAML which further activate the transcription process of the targeted genes. (d) The Wnt pathway (extreme right): Wnt ligand binds to Fz, a receptor, and induces the phosphorylation of the coreceptors, LRP5/6, which further forms the docking site for AXIN. The binding of the ligand to the receptor signals Dvl to recruit AXIN 1 along with the other kinases CK1α and GSK3β to the membrane, which interrupts the destruction complex leading to impairment of the phosphorylation of β-catenin and results in its destruction. Accumulated β-catenin then translocates from the cytoplasm to the nucleus and functions as an activator of TCF/LEF-mediated transcription of Wnt target genes.