Activation of STAT3 by cadherin engagement

STAT3 is a latent cytoplasmic transcription factor, activated by receptor tyrosine kinases such as EGFR, or PDGFR, cytokine receptors such as the Interleukin-6 receptor family (IL6R or gp130 – also known as IL6ST), and non-receptor tyrosine kinases such as SRC. Activation entails phosphorylation of the critical tyrosine-705 residue (p-Y705) of STAT3 by the receptor itself or an associated Jak kinase, dimerization and translocation to the nucleus. The dimers subsequently bind specific DNA sequences to activate the transcription of specific genes involved in cell division and survival, while they downregulate the tumor suppressor p53, thus protecting tumor cells from apoptosis (reviewed in Yu et al. 2009, Bharadwaj et al. 2020). Hyperactivation of STAT3 is present in a large number of cancers and has been reported to be required for tumour cell growth, survival, angiogenesis, metastasis and immune evasion (reviewed in Bharadwaj et al. 2020), while a hyperactive form of Stat3 (Stat3C) is able to transform cultured cells.

Activation of Stat3 by cadherin engagement

Early results demonstrated that cell to cell contact, as occurs with confluence, or aggregation of cultured cells, leads to a dramatic increase in phosphorylation of STAT3 at the activating tyrosine-705 (p-Y705-STAT3), DNA binding and transcriptional activity, in both non-transformed mouse or rat fibroblasts or MCF-10A human breast cells, as well as in a series of four human breast cancer cell lines, and a number of human lung cancer cell lines.

It was later definitively demonstrated that STAT3 is activated by direct homophilic interactions of E-cadherin (CDH1) molecules of the opposing cells, even in the absence of direct cell to cell contact. This was shown by plating mouse epithelial HC11 cells onto surfaces coated with fragments encompassing the two outermost domains of CDH1. In fact, CDH1 engagement was shown to trigger a dramatic surge in total RAC1 and CDC42 protein levels and activity through inhibition of proteolytic degradation, and this was responsible for the STAT3 activation observed. It was further demonstrated that the increase in RAC1/Cdc42 activity leads to transcriptional upregulation of members of the IL6 family of cytokines through the transcription factor NFκB and activation of the common receptor, gp130 (IL6ST), leading to STAT3 activation, in an autocrine manner. STAT3 then dimerizes, migrates to the nucleus and activates transcription of genes involved in cell division, survival, proliferation and migration (Arulanandam et al. 2009, Arulanandam et al. 2010, reviewed in Raptis et al. 2009, Raptis et al. 2011). In sharp contrast to STAT3, the activity of Erk1/2 (extracellular signal activated kinase, officially MAPK1/MAPK3) was unaffected by cell density, or cadherin engagement. Two mesenchymal cadherins, cadherin-11 (CDH11) and N-cadherin (CDH2) were also found to activate STAT3 in different cells, by similar mechanisms (Geletu, Arulanandam et al. 2013, reviewed in Geletu, Guy et al. 2013).