Signal Transduction

J.M. Graff, A. Bansal, D.A. Melton, "Xenopus Mad Proteins Transduce Distinct Subsets of Signals for the TGFß Superfamily," Cell,85:479-87, 1996. (Cited in at least 120 publications to date) Comments by Jonathan M. Graff, Center for Developmental Biology, Department of Molecular Biology and Oncology, University of Texas Southwestern Medical Center, Dallas FROG FLIPSIDE: Jonathan M. Graff of the University of Texas Southwestern Medical Center discovered that Xmad1 induced ventral mesoderm while Xmad2 induced dorsal mesoderm in frog embryos. To the untrained eye, frogs and flies have little in common. But to cellular and molecular biologists, these creatures offer scientists significant insight on intracellular signaling cascades that mediate a diverse array of biological processes in animals from insect to human. Jonathan M. Graff, an investigator at the Center for Developmental Biology in the department of molecular biology and oncology at the University of Texas Southwestern Medical Center in Dallas, is one of those scientists. He recently led a research team that completed a study that has increased understanding of the signal transduction of transforming growth factor ß (TGFß). The TGFß superfamily consists of more than 25 related proteins that mediate the development of biological processes such as immune function, growth control, cell differentiation, and skeletal formation. In collaboration with Douglas A. Melton, a Howard Hughes Medical Institute investigator at Harvard University, Graff's research team discovered two major components of the growth factor's signaling cascade, defined the function and position of each of these components, and accumulated evidence that suggests that each is highly conserved through evolution in vertebrates and invertebrates. In the past, the TGFß signaling cascade had attracted the attention of numerous research teams. Unlike other cytokines such as fibrogrowth factors, insulin, and adrenaline, the intracellular components of the cascade have remained essentially unknown. Other laboratories discovered several good candidates, but experiments failed to provide evidence of their function in the TGFß signaling cascade. One of the leading candidates has been the Drosophila gene Mothers against DPP (Mad). Recent studies have shown that the Drosophila Mad gene is present in cytoplasm and appears to be necessary for any cell differentiation response to DPP in mesoderm and endoderm (S.J. Newfeld et al., Development, 122:2099-2108, 1996). Because Mad genes appear to be conserved in flies and worms, Graff's research team decided to search for related genes in the Xenopus laevis frog. They identified four distinct Mad-related proteins (Xmads) in the frogs. Analysis of two of the four Xmads established that Mad is highly conserved from flies to frogs. The sequence of the first Xmad (Xmad1), now known as Smad1, is 76 percent identical in amino acid sequence to Drosophila Mad. The second Xmad (Xmad2), now known as Smad2, is 62 percent identical to Drosophila Mad. Xmad1 and Drosophila Mad function identically in frog embryonic assays. "The conserved function and this high degree of similarity between Mad and Xmad genes suggests to us that the genes are homologous and conserved from invertebrates to vertebrates," Graff notes. The major finding of Graff's study was that the two Xmads function in discrete pathways and produce distinct effects on cellular development. For example, when Xmad1 is expressed in developing eggs, ventral mesoderm formed. In contrast, when Xmad2 is expressed, cell tissue elongates in a manner characteristic of dorsal mesoderm, the middle of the three primary layers of cell differentiation in embryos. The research team also sought to determine the relative position of Xmads within the TGFß signaling cascade. Experiments suggest that Xmad1 works downstream of BMP receptors. While truncated activin receptors block both activin and Vg1 function and prevent the development of dorsal mesoderm; a similar effect on Xmad2 and the development of dorsal mesoderm was not observed, suggesting that Xmad2 functions downstream in the activin/Vg1 pathway. Graff explains that the study has attracted widespread interest from researchers for a variety of reasons. The most obvious is that understanding of the TGF ß signaling cascade has eluded scientists for many years. "A plethora of laboratories attempted to elucidate this signaling pathway for over a decade," Graff states. "In addition, Smads are tumor suppressor genes and are mutated in a variety of human concessions. . . . Therefore, the Mad-related genes hold promise as an intracellular target for therapeutic compounds." For example, recent amino acid comparison suggests that DPC4, a tumor suppresser gene that is deleted in pancreatic cancers, is homologous to Xmad4 (S. Hahn et al., Science, 271: 350-53, 1996).

Signal Transduction

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