Fig. 1

STAT3 structure and the canonical and non-canonical STAT3 signaling pathways in cancer. A Diagrams of structure and function domains of STAT3 with the posttranslational modification residue sites. STAT3 is composed of an N-terminal domain (NTD), DNA binding domain, linker domain, Src homology 2 domain (SH2), and a C-terminal transactivation domain (TAD) with a tyrosine phosphorylation residue at 705 and a serine phosphorylation residue at 727. Red font represents activation PTM sites, blue font represents inactive PTM sites. B Left part, the canonical STAT3 signaling pathway is activated by multiple receptors including interleukin-6 (IL-6) and IL-6 family cytokines (IL-11, IL-23) receptors, G-coupled receptors (GPCRs), growth factor receptors and Toll-liker receptors which are stimulated by cognate ligands varies from cytokines, hormones, angiotensin, sphingosine-1-phosphate, and LPS et al. Traditionally, these receptors lack the intrinsic kinase activity. Once the ligands recognize the cognate receptors, the ligand-receptor shifts conformation and activate the JAKs, then provide the anchor site for STAT3 to bind via its SH2 domain. In addition to being activated by the membrane receptors, the constitutive activation of STAT3 is also induced by oncoproteins with tyrosine kinase activity like SRC and BCR-ABL. Two phosphorylated STAT3 form dimers via the phosphorylated tyrosine residue 705 of one monomer interacts with the SH2 domain of another monomer, the dimers subsequently translocate into the nucleus and bind to the specific DNA response elements in the promotor regions of the target genes which are involved in proliferation, metastasis, angiogenesis, tumor immune suppression, metabolic reprogramming, cancer stemness, drug resistance and exosome activity. Right part, the non-canonical STAT3 signaling pathway has three forms including mtSTAT3, unphosphorylated STAT3 and p-STAT3 Ser727 either alone or together with p-STAT3 Tyr705. These forms of STAT3 regulate the mitochondrial respiration, NF-κB, and other unknown genes are involved in activities. Created with BioRender.com