Specificity in Transforming Growth Factor–β Signaling Pathways

Because the number of identified TGF-β ligands far exceeds the number of identified receptors and signal transducers, it appears that cells do not have the luxury to respond to each ligand through a unique signal-transduction pathway; yet, cells still are able to respond to various TGF-β superfamily members in characteristic ways. Thus, cells must take advantage of the multiple combination opportunities available in this pathway, not only to generate specific responses to a range of TGF-β ligands but also to respond differently to the same ligand as the cellular context changes. As we have illustrated, the specificity of TGF-β signaling can be modulated at various levels, but fundamental questions remain regarding many of the molecular interactions and their role in signaling specificity. For example, although it is well recognized that TGF-β signaling requires an active heterotetrameric complex consisting of dimeric forms of type I and type II receptors, multiple forms of heterotetrameric receptor complexes potentially can be generated by various combinations of type I and type II receptors, as has been suggested for the case of the ActR-IIB receptor, which can function in association with either ActR-I or ActR-IB to confer different cellular responses (Carcamo et al. 1994xType I receptors specify growth inhibitory and transcriptional responses to TGF-β and activin. Carcamo, J, Weis, FMB, Ventura, F, Wieser, R, Wrana, JL, Attisano, L, and Massague. Mol Cell Biol. 1994; 14: 3810–3821Crossref | PubMedSee all References1994; Armes and Smith 1997xThe ALK-2 and ALK-4 activin receptors transduce distinct mesoderm-inducing signals during early Xenopus development but do not cooperate to establish thresholds. Armes, NA and Smith, JC. Development. 1997; 124: 3797–3804PubMedSee all References1997). Furthermore, although both type I and type II receptors exist as dimers, whether each receptor type forms homodimers exclusively or whether heterodimeric forms exist is not clear.At the intracellular level, our understanding of the mechanisms by which smads control specific gene induction is limited. For instance, smads have been shown to have both intrinsic DNA-binding capability, as well as transcriptional transactivation activity (Whitman 1998xSmads and early developmental signaling by the TGF-β superfamily. Whitman, M. Genes Dev. 1998; 12: 2445–2462Crossref | PubMedSee all References1998), but they also have been shown to associate with various nuclear transcription factors, which together effect target-gene activation (Chen et al. 1996xA transcriptional partner for MAD proteins in TGF-β signaling. Chen, X, Rubock, MJ, and Whitman, M. Nature. 1996; 383: 691–696Crossref | PubMed | Scopus (580)See all References1996; Whitman 1998xSmads and early developmental signaling by the TGF-β superfamily. Whitman, M. Genes Dev. 1998; 12: 2445–2462Crossref | PubMedSee all References1998). Therefore, whether activation of smads is sufficient in itself to activate target genes in vivo is uncertain, as are the relative contributions of the smad DNA-binding domain and the transactivation domain, in the activation of target genes. Furthermore, Tsukazaki et al. (1998xSARA, a FYVE domain protein that recruits smad2 to the TGF-β receptor. Tsukazaki, T, Chiang, TA, Davison, AF, Attisano, L, and Wrana, JL. Cell. 1998; 95: 779–791Abstract | Full Text | Full Text PDF | PubMed | Scopus (662)See all References1998) recently showed that the regulation of the subcellular localization of the pathway-specific smad smad2 is important in the transduction of TGF-β signals. The FYVE-domain protein SARA (smad anchor receptor activation) functions in this localization by regulating the interaction of smad2 with the receptor complex at the membrane and smad4 in the cytoplasm. These authors propose that phosphorylation of smad2 by the type I receptor results in dissociation from SARA, with a concomitant formation of a smad2/4 complex and nuclear translocation. The mechanism by which smads are translocated to the nucleus, where they affect gene expression, remains unknown. These and other issues remain to be addressed, and we anticipate that, as in the past, the conclusions from work with Xenopus will dovetail with findings from other systems as these fundamental questions are answered.