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First published online September 28, 2007
doi: 10.1242/10.1242/dev.005926

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TGFß superfamily signaling: notes from the desert

¹ Waksman Institute, Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway, NJ 08854-8020, USA.
² The Cancer Institute of New Jersey, UMDNJ-Robert Wood Johnson Medical School, New Brunswick, NJ 08903, USA.
³ Departments of Internal Medicine and Molecular Genetics, Microbiology and Immunology, UMDNJ-Robert Wood Johnson Medical School, New Brunswick, NJ 08903, USA.

View larger version (70K): [in this window] [in a new window]   Fig. 1. Modulation of Smad signaling. TGFß/Smad superfamily signal strength is regulated and modulated at several different levels, both intrinsically and through cross-talk with other signaling pathways. R-Smads and co-Smads continuously shuttle between cytoplasm and nucleus. Following TGFß ligand-mediated engagement of the type II/type I receptor complex and R-Smad activation, C-terminally phosphorylated R-Smads are preferentially retained in the nucleus, where they initiate a specific transcription program. Signal termination at the level of receptors results in rapid dephosphorylation of activated R-Smads in the nucleus by the nuclear phosphatase, PPM1A. In addition, cells adapt to their persistent exposure to TGFß ligands by eliminating activated R-Smads by proteasomal degradation. This adaptive response may be mediated by TGFß-initiated non-Smad-dependent activation of MAP kinase pathways, which phosphorylate specific tyrosine residues in the Smad linker regions. These phosphorylation events appear to trigger proteasomal degradation and prevent nuclear transport of activated R-Smads, and are turned off by SCP-type phosphatases. Similar mechanisms centered on R-Smad linker regions appear to be utilized by mitogenic and stress stimuli to counterbalance the effects of TGFß signals. Conversely, MAP kinase-mediated N-terminal phosphorylation of p53 enables its interaction with activated R-Smads, thereby enhancing their cytostatic functions. This pathway may serve as a negative feed-forward loop to counterbalance excessive mitogenic signaling.