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. 2019 Oct 29;11(11):1681. doi: 10.3390/cancers11111681

Figure 1.

Figure 1

Pathways of signal transducer and activator of transcription 3 (STAT3) activation. Activation of STAT3 occurs via the initial phosphorylation of tyrosine 705 on the STAT3 molecule. This can occur in several ways: (1) Ligand binding activates Janus kinases (JAKs) that are associated with a receptor that lacks intrinsic tyrosine kinase activity, such as the interleukin-6 (IL-6) receptor/gp130 complex; (2) Activated JAKs phosphorylate the cytoplasmic region of the receptor molecule which then serves as a recruitment site for STAT3; (3) STAT3 is then phosphorylated by JAK. (4) Receptor tyrosine kinases (RTK) such as epidermal growth factor receptor (EGFR) or vascular endothelial growth factor receptor (VEGFR) have intrinsic kinase capabilities which directly phosphorylate STAT3 following ligand binding. (5) Receptor independent tyrosine kinases such as c–SRC can phosphorylate JAK without receptor activation. Once Y705 of STAT3 is phosphorylated the SH2 domain of each STAT3 molecule binds the phospho-tyrosine of another, resulting in dimerization of the two proteins. These homodimers are then able to translocate to the nucleus and bind the promoter regions of target genes and induce their transcription. Many of these target genes encode proteins that drive cellular proliferation and survival.