Fig. 1

Signaling pathways in colorectal CSCs. A Wnt/β-catenin signaling pathway. In the presence of Wnt ligand proteins, the engagement of Wnt, Frizzled and LRP5/6 on the cell surface induces the activation of downstream DVL signaling, which in turn inhibits the β-catenin destruction complex (which is mainly composed of APC, Axin1/2, GSK3β and CK1α), allowing β-catenin to avoid being degraded, to accumulate in the cytoplasm and enter the nucleus. β-catenin enters the nucleus and binds with TCF/LEF to promote the transcription and expression of target genes. B Hippo/Yap signaling pathway. Upon stimulation via upstream signaling (mainly cell polarity, cell contact, and mechanical force signals), phosphorylated MST1/2 phosphorylate LATS1/2, and then, activated LATS1/2 phosphorylate YAP/TAZ to induce their degradation. In the absence of upstream signal stimulation, dephosphorylated YAP/TAZ aggregate in the nucleus and combine with the transcription factors TEAD1-4 to promote the expression of target genes. C JAK/STAT signaling pathway. When cytokines bind plasma membrane the receptors, receptors dimerize, and receptor-associated JAK kinase is activated via mutual phosphorylation. Then, the activated JAK kinase phosphorylates receptor tyrosine residues and recruits and activates SH2 domain-containing STAT, which dissociates from the receptor, forms dimers in the cytoplasm and enters the nucleus to regulate the expression of target genes. D Notch signaling pathway. Delta-like ligands (DLL1, DLL2, DLL3 and DLL4) and Jagged ligands (JAG1 and JAG2) adjacent to cells are ligands for Notch receptors (including Notch 1, Notch 2, Notch 3 and Notch 4). Through a combination of ligands and receptors, the S2 site in Notch receptors is cleaved by the ADAM10 or ADAM17 protease, resulting in the release of the extracellular portion of Notch. Then, γ-secretase cleaves the Notch receptor at the S3 site, allowing the release of the Notch intracellular domain (NICD). The NICD enters the nucleus and interacts with CSL to regulate the expression of downstream target genes