Cadherin-cadherin engagement promotes cell survival via Rac1/Cdc42 and signal transducer and activator of transcription-3.
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).
Arulanandam
Rozanne
R
Department of Microbiology and Immunology, Department of Pathology and Molecular Medicine, and Cancer Research Institute, Queen's University, Ontario, Canada K7L 3N6.
Vultur
Adina
A
Cao
Jun
J
Carefoot
Esther
E
Elliott
Bruce E
BE
Truesdell
Peter F
PF
Larue
Lionel
L
Feracci
Hélène
H
Raptis
Leda
L
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015820:Cadherins / Q000378:metabolism*; D002448:Cell Adhesion / Q000187:drug effects; D002452:Cell Count; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004848:Epithelium / Q000187:drug effects / Q000201:enzymology; D005260:Female; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000187:drug effects; D053612:Janus Kinases / Q000378:metabolism; D008321:Mammary Glands, Animal / Q000166:cytology; D051379:Mice; D010455:Peptides / Q000494:pharmacology; D019000:Phosphotyrosine / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D012995:Solubility / Q000187:drug effects; D020764:cdc42 GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*
D015820:Cadherins; D016207:Cytokines; D010455:Peptides; D050796:STAT3 Transcription Factor; D019000:Phosphotyrosine; D053612:Janus Kinases; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein