Switching Numbers

Sci. Signal.  27 Jan 2009:
Vol. 2, Issue 55, pp. ec30
DOI: 10.1126/scisignal.255ec30

Transforming growth factor–β (TGF-β) signaling in normal mammary epithelial cells inhibits tumor cell formation. As breast cancer becomes established, however, TGF-β promotes cellular proliferation and migration, an alteration in signaling outcomes whose cause is unclear. TGF-β signals through a heterodimeric receptor consisting of the type I receptor kinase ALK5 and the type II receptor kinase, TβRII. In canonical TGF-β signaling, activation of the receptor triggers the recruitment of Smad2 and Smad3 proteins to ALK5 (mediated by its L45 loop), their phosphorylation (and activation), and their translocation to the nucleus to mediate target gene transcription. Liu et al. found that, in addition to activating Smad3, TGF-β also activated Smad1 and Smad5 in tumorigenic mouse mammary epithelial (4T1) cells. These proteins are thought of as canonical targets of TGF-β–related bone morphogenetic proteins (BMPs), which activate type I receptors (other than ALK5) with L45 loops specific for these Smads. The authors also showed that TGF-β stimulated the migration of 4T1 cells, and experiments with short hairpin RNAs demonstrated that ALK5 was required for TGF-β–mediated activation of Smad1 and Smad5 and that both Smads contributed substantially to migration. Expression of mutant ALK5 proteins showed that its L45 loop was required for TGF-β–mediated migration, and ALK5 phosphorylated Smad1 and Smad5 in vitro. TGF-β stimulated the phosphorylation of Smad1 and Smad5 in a range of tumorigenic cell lines but not in immortalized cell lines. In addition, TGF-β–mediated activation of these Smads was stronger in cells expressing the HER2 oncogene than in control cells. This study suggests that TGF-β–stimulated activation of Smad1 and Smad5 rather than of its canonical Smads may contribute to the switch to a migratory phenotype seen in tumorigenic cells.

I. M. Liu, S. H. Schilling, K. A. Knouse, L. Choy, R. Derynck, X.-F. Wang, TGFβ-stimulated Smad1/5 phosphorylation requires the ALK5 L45 loop and mediates the pro-migratory TGFβ switch. EMBO J. 28, 88–98 (2009). [PubMed]