Abstract
Signal transducer and activator of transcription-3 (Stat3) is activated by a number of receptor and nonreceptor tyrosine kinases, whereas a constitutively active form of Stat3 alone is sufficient to induce neoplastic transformation. In the present report, we show that Stat3 can also be activated through homophilic interactions by the epithelial (E)-cadherin. Indeed, by plating cells onto surfaces coated with fragments encompassing the two outermost domains of this cadherin, we clearly show that cadherin engagement can activate Stat3, even in the absence of direct cell-to-cell contact. Most importantly, our results also reveal for the first time an unexpected and dramatic surge in total Rac1 and Cdc42 protein levels triggered by cadherin engagement and an increase in Rac1 and Cdc42 activity, which is responsible for the Stat3 stimulation observed. Inhibition of cadherin interactions using a peptide, a soluble cadherin fragment, or genetic ablation induced apoptosis, points to a significant role of this pathway in cell survival signaling, a finding that could also have important therapeutic implications. (Mol Cancer Res 2009;7(8):1310-27).
Highlights
The signal transducer and activator of transcription-3 (Stat3) is found to be overexpressed in a number of carcinomas and tumor cell lines
E-cadherin Engagement Can Activate Stat3 To explore the nature of the molecule(s) that might be involved in the cell density–mediated Stat3 activation, we used the normal mouse breast epithelial line HC11, which expresses high amounts of epithelial (E)-cadherin, an extensively studied, calcium-dependent, cell-to-cell adhesion molecule and member of the classic type I cadherin family
HC11 cells were plated in plastic Petri dishes, and when ∼30% to 80% confluent, and over several days thereafter, detergent cell extracts were probed by Western blotting with an antibody specific for the Tyr705 phosphorylated form of Stat3 (Stat3-pTyr705; see Materials and Methods)
Summary
The signal transducer and activator of transcription-3 (Stat3) is found to be overexpressed in a number of carcinomas and tumor cell lines (reviewed in ref. 1, 2). The signal transducer and activator of transcription-3 (Stat3) is found to be overexpressed in a number of carcinomas and tumor cell lines Stat is invariably latent in the cytoplasm and, subsequent to binding to an activated receptor through its Src homology 2 (SH2) domain, becomes activated through phosphorylation by the receptor itself or by the associated Janus kinase (JAK) or Src family kinases. Phosphorylation at the critical Tyr705 activates Stat by stabilizing the association of two monomers through reciprocal SH2-phosphotyrosine interactions. The Stat dimer migrates to the nucleus where it binds to target sequences, leading to the transcriptional activation of specific genes, such as myc, Bcl-xL, cyclin D, survivin, hepatocyte growth factor (HGF), and others [1]
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