Editors' ChoiceCell Migration

TGF-β Signaling Not Required

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Sci. Signal.  26 May 2009:
Vol. 2, Issue 72, pp. ec172
DOI: 10.1126/scisignal.272ec172

The type III transforming growth factor (TGF)–β receptor (TβRIII) presents ligands to types I and II TGF-β receptors, which then activate Smad transcription factors. Loss of TβRIII correlates to poor clinical outcome in multiple cancers, and restoration of TβRIII decreases cancer cell motility and invasion in vitro. Mythreye and Blobe found that migration was reduced in ovarian (Ovca429) and breast (MDA-MB231) cancer cell lines overexpressing TβRIII, whereas it was enhanced in normal ovarian epithelial cells (NOSE007) transfected with a short hairpin RNA (shRNA) directed against TβRIII. In addition, NOSE007 cells transfected with the TβRIII shRNA exhibited altered morphology, such as increased formation of stress fibers and lamellipodia compared with control cells. Various manipulations expected to block classical TGF-β signaling [such as treatment with the TβRI inhibitor SB431542, expression of a dominant-negative TβRII construct, incubation with a function-neutralizing TGF-β receptor antibody, or transfection of a small interfering RNA (siRNA) against Smad2] did not affect the ability of TβRIII to inhibit migration. In contrast, expression of a dominant-negative form of the small guanosine triphosphatase Cdc42, but not a dominant-negative form of Rac1, abrogated the inhibitory effect of TβRIII overexpression on migration in Ovca429 cells. Transfection of an siRNA targeting β-arrestin 2, a previously identified binding partner of TβRIII, prevented Cdc42 activation and reduced migration in TβRIII-overexpressing Ovca429 cells. The authors suggest that activation of Cdc42 through β-arrestin 2 may constitute a tumor suppressor function of TβRIII that is independent of TGF-β.

K. Mythreye, G. C. Blobe, The type III TGF-β receptor regulates epithelial and cancer cell migration through β-arrestin2-mediated activation of Cdc42. Proc. Natl. Acad. Sci. U.S.A. 106, 8221–8226 (2009). [Abstract] [Full Text]