Fig. 1

Developmental signaling that govern CSCs and therapy resistance. a. Hippo signlaing consists of a core kinase cascade in which Mst1/2 forms a complex with the adaptor SAV1 that phosphorylates the kinases LATS1/2. LATS1/2 then phosphorylates and represses the transcriptional coactivators YAP1 and TAZ by promoting their degradation and cytoplasmic retention. When deregulation of the Hippo signaling by deletion or mutation of these kinases, YAP/TAZ accumulate in the nuclear and binds to its transcription factor Tead1–4 and upregulation of its target genes involving cell proliferation, CSCs properties and drug resistance. b. When SHH reaches its target cell, it binds to the PTCH1 receptor. The binding of SHH relieves SMO inhibition, leading to activation of the GLI transcription factors. Activated GLI accumulates in the nucleus and controls the transcription of hedgehog target genes. c. The Wnt/β-catenin pathway is important for CSC maintenance. In the canonical pathway, Wnt ligands bind to transmembrane Frizzled receptor, leading to the recruitment of Dvl protein. Dvl triggers the cytoplasmic accumulation of β-catenin which translocates into the nucleus, where it forms a complex with TCF/LEF that control genes in CSCs and therapy resistance. d. Notch signaling is activated through cell-to-cell contact. Ligands bind to Notch receptors on the target cell. This allows intracellular cleavage through γ-secretase, producing NICD. NICD translocates to the nucleus binding with CSL complex, triggering transcription and leading to CSC maintenance, metastasis and chemo-resistance. e. JAK-STAT signaling is made of three major proteins: cell-surface receptors, JAKs, and STATs. Once a ligand binds to the receptor, JAKs phosphorylates the receptor (gp130) which allows STAT proteins binds and be phosphorylated by JAKS to form a dimer. The phosphorylated STAT dimer enters the nucleus, binds to DNA, and causes transcription of target genes