Fig. 3. Signaling pathways that lead to STAT3 activation.
a. STAT3 can be phosphorylated at Y705 directly by RTKs (EGFR and EGFRvIII) and non-receptor TK (JAK2) and becomes activated. Inactive JAK2 is constitutively bound to the G-protein coupled receptors (IL-R, LIF-R, gp130) and becomes auto-phosphorylated at Y1007/1008 upon receptor activation. In addition, JAK2 can be phosphorylated at Y1007/1008 directly by RTKs (EGFR/EGFRvIII and PDGFR) and non-receptor TK, Src.
b. STAT3 activation via S727 phosphorylation can be initiated by stimulation of EGF (via Akt, ERK, JNK and p38) and IL-6 (via PKCε).