Early results demonstrated that mutationally activated, oncogenic chicken SRC (SRC-Y527F) activates STAT3 and requires STAT3 activity for neoplastic conversion (Turkson et al. 1998, Bromberg et al. 1998). Regarding the mechanism, it was later shown that SRC-Y527F increases RAC levels, leading to secretion of IL6, which leads to STAT3 activation. Interestingly however, SRC-Y527F also downregulates cadherins (CDH11 and CDH1), in a quantitative manner, while cadherins are required for the integrity of IL6ST for IL6 family signalling. As a result, SRC-Y527F expression to intermediate levels allows sufficient CDH11, hence IL6ST levels, for STAT3 activation, as previously reported (Turkson et al. 1998, Bromberg et al. 1998). However, expressed to high levels, SRC-Y527F eliminates CDH11, hence IL6ST signaling, thus eliminating p-Y705-STAT3 entirely.

Taken together, these data reveal the existence of a loop between SRC, CDH11, IL6/IL6ST and STAT3. This fine balance between SRC-Y527F and CDH11 levels which is required for STAT3 activation and cellular survival, results in an increase (rather than a decrease) in p-Y705-STAT3 in cells with high-chicken SRC-Y527F upon SRC inhibition (Adan et al. 2022), a finding which could have significant therapeutic implications regarding inhibitors of activated SRC (Adan, Guy et al. 2022, reviewed in Adan et al. 2022).

It is interesting to note that a number of oncogenes, such as the membrane-bound, middle Tumor Antigen of the mouse polyoma virus, transform cells through binding to and increasing the kinase activity of the cellular SRC (Raptis et al. 1985). In addition, it was also demonstrated that nuclear oncogenes such as SVLT (Simian Virus 40 Large Tumor antigen) are also able to activate STAT3 (Vultur et al. 2005), and that SVLT requires c-SRC for oncogenic transformation (Arulanandam et al. 2010).

Interestingly, a cellular STAT3 inhibitor, the Caveolin-1 (CAV1) protein, reduces IL6ST and p-Y705-STAT3 by binding to and sequestering cadherins onto its scaffolding domain (Geletu et al. 2018). Therefore, it appears that the road to STAT3 is “paved with cadherins”, either to increase, or to decrease, STAT3 activity (reviewed in Adan et al. 2022).