Abstract
Although transforming growth factor beta (TGF-beta) superfamily ligands play critical roles in diverse developmental processes, how cells transduce signals from these ligands is still poorly understood. Cell surface receptors for these ligands have been identified, but their cytoplasmic targets are unknown. We have identified three Caenorhabditis elegans genes, sma-2, sma-3, and sma-4, that have mutant phenotypes similar to those of the TGF-beta-like receptor gene daf-4, indicating that they are required for daf-4-mediated developmental processes. We show that sma-2 functions in the same cells as daf-4, consistent with a role in transducing signals from the receptor. These three genes define a protein family, the dwarfins, that includes the Mad gene product, which participates in the decapentaplegic TGF-beta-like pathway in Drosophila [Sekelsky, J. J., Newfeld, S. J., Raftery, L. A., Chartoff, E. H. & Gelbart, W. M. (1995) Genetics 139, 1347-1358]. The identification of homologous components of these pathways in distantly related organisms suggests that dwarfins may be universally required for TGF-beta-like signal transduction. In fact, we have isolated highly conserved dwarfins from vertebrates, indicating that these components are not idiosyncratic to invertebrates. These analyses suggest that dwarfins are conserved cytoplasmic signal transducers.
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- Austin J., Kimble J. glp-1 is required in the germ line for regulation of the decision between mitosis and meiosis in C. elegans. Cell. 1987 Nov 20;51(4):589–599. doi: 10.1016/0092-8674(87)90128-0. [DOI] [PubMed] [Google Scholar]
- Baird S. E., Fitch D. H., Kassem I. A., Emmons S. W. Pattern formation in the nematode epidermis: determination of the arrangement of peripheral sense organs in the C. elegans male tail. Development. 1991 Oct;113(2):515–526. doi: 10.1242/dev.113.2.515. [DOI] [PubMed] [Google Scholar]
- Brenner S. The genetics of Caenorhabditis elegans. Genetics. 1974 May;77(1):71–94. doi: 10.1093/genetics/77.1.71. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Brummel T. J., Twombly V., Marqués G., Wrana J. L., Newfeld S. J., Attisano L., Massagué J., O'Connor M. B., Gelbart W. M. Characterization and relationship of Dpp receptors encoded by the saxophone and thick veins genes in Drosophila. Cell. 1994 Jul 29;78(2):251–261. doi: 10.1016/0092-8674(94)90295-x. [DOI] [PubMed] [Google Scholar]
- Clark-Lewis I., Sanghera J. S., Pelech S. L. Definition of a consensus sequence for peptide substrate recognition by p44mpk, the meiosis-activated myelin basic protein kinase. J Biol Chem. 1991 Aug 15;266(23):15180–15184. [PubMed] [Google Scholar]
- Coulson A., Sulston J., Brenner S., Karn J. Toward a physical map of the genome of the nematode Caenorhabditis elegans. Proc Natl Acad Sci U S A. 1986 Oct;83(20):7821–7825. doi: 10.1073/pnas.83.20.7821. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Coulson A., Waterston R., Kiff J., Sulston J., Kohara Y. Genome linking with yeast artificial chromosomes. Nature. 1988 Sep 8;335(6186):184–186. doi: 10.1038/335184a0. [DOI] [PubMed] [Google Scholar]
- Estevez M., Attisano L., Wrana J. L., Albert P. S., Massagué J., Riddle D. L. The daf-4 gene encodes a bone morphogenetic protein receptor controlling C. elegans dauer larva development. Nature. 1993 Oct 14;365(6447):644–649. doi: 10.1038/365644a0. [DOI] [PubMed] [Google Scholar]
- Georgi L. L., Albert P. S., Riddle D. L. daf-1, a C. elegans gene controlling dauer larva development, encodes a novel receptor protein kinase. Cell. 1990 May 18;61(4):635–645. doi: 10.1016/0092-8674(90)90475-t. [DOI] [PubMed] [Google Scholar]
- Hodgkin J. Male Phenotypes and Mating Efficiency in CAENORHABDITIS ELEGANS. Genetics. 1983 Jan;103(1):43–64. doi: 10.1093/genetics/103.1.43. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ignotz R. A., Massagué J. Transforming growth factor-beta stimulates the expression of fibronectin and collagen and their incorporation into the extracellular matrix. J Biol Chem. 1986 Mar 25;261(9):4337–4345. [PubMed] [Google Scholar]
- Irish V. F., Gelbart W. M. The decapentaplegic gene is required for dorsal-ventral patterning of the Drosophila embryo. Genes Dev. 1987 Oct;1(8):868–879. doi: 10.1101/gad.1.8.868. [DOI] [PubMed] [Google Scholar]
- Koenig B. B., Cook J. S., Wolsing D. H., Ting J., Tiesman J. P., Correa P. E., Olson C. A., Pecquet A. L., Ventura F., Grant R. A. Characterization and cloning of a receptor for BMP-2 and BMP-4 from NIH 3T3 cells. Mol Cell Biol. 1994 Sep;14(9):5961–5974. doi: 10.1128/mcb.14.9.5961. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Letsou A., Arora K., Wrana J. L., Simin K., Twombly V., Jamal J., Staehling-Hampton K., Hoffmann F. M., Gelbart W. M., Massagué J. Drosophila Dpp signaling is mediated by the punt gene product: a dual ligand-binding type II receptor of the TGF beta receptor family. Cell. 1995 Mar 24;80(6):899–908. doi: 10.1016/0092-8674(95)90293-7. [DOI] [PubMed] [Google Scholar]
- Lin H. Y., Lodish H. F. Receptors for the TGF-beta superfamily: multiple polypeptides and serine/threonine kinases. Trends Cell Biol. 1993 Jan;3(1):14–19. doi: 10.1016/0962-8924(93)90195-7. [DOI] [PubMed] [Google Scholar]
- Liu F., Ventura F., Doody J., Massagué J. Human type II receptor for bone morphogenic proteins (BMPs): extension of the two-kinase receptor model to the BMPs. Mol Cell Biol. 1995 Jul;15(7):3479–3486. doi: 10.1128/mcb.15.7.3479. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mello C. C., Kramer J. M., Stinchcomb D., Ambros V. Efficient gene transfer in C.elegans: extrachromosomal maintenance and integration of transforming sequences. EMBO J. 1991 Dec;10(12):3959–3970. doi: 10.1002/j.1460-2075.1991.tb04966.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nellen D., Affolter M., Basler K. Receptor serine/threonine kinases implicated in the control of Drosophila body pattern by decapentaplegic. Cell. 1994 Jul 29;78(2):225–237. doi: 10.1016/0092-8674(94)90293-3. [DOI] [PubMed] [Google Scholar]
- Padgett R. W., St Johnston R. D., Gelbart W. M. A transcript from a Drosophila pattern gene predicts a protein homologous to the transforming growth factor-beta family. Nature. 1987 Jan 1;325(6099):81–84. doi: 10.1038/325081a0. [DOI] [PubMed] [Google Scholar]
- Pawson T. Protein modules and signalling networks. Nature. 1995 Feb 16;373(6515):573–580. doi: 10.1038/373573a0. [DOI] [PubMed] [Google Scholar]
- Penton A., Chen Y., Staehling-Hampton K., Wrana J. L., Attisano L., Szidonya J., Cassill J. A., Massagué J., Hoffmann F. M. Identification of two bone morphogenetic protein type I receptors in Drosophila and evidence that Brk25D is a decapentaplegic receptor. Cell. 1994 Jul 29;78(2):239–250. doi: 10.1016/0092-8674(94)90294-1. [DOI] [PubMed] [Google Scholar]
- Pinna L. A. Casein kinase 2: an 'eminence grise' in cellular regulation? Biochim Biophys Acta. 1990 Sep 24;1054(3):267–284. doi: 10.1016/0167-4889(90)90098-x. [DOI] [PubMed] [Google Scholar]
- Raftery L. A., Twombly V., Wharton K., Gelbart W. M. Genetic screens to identify elements of the decapentaplegic signaling pathway in Drosophila. Genetics. 1995 Jan;139(1):241–254. doi: 10.1093/genetics/139.1.241. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Riddle D. L., Swanson M. M., Albert P. S. Interacting genes in nematode dauer larva formation. Nature. 1981 Apr 23;290(5808):668–671. doi: 10.1038/290668a0. [DOI] [PubMed] [Google Scholar]
- Roberts A. B., Sporn M. B. Physiological actions and clinical applications of transforming growth factor-beta (TGF-beta). Growth Factors. 1993;8(1):1–9. doi: 10.3109/08977199309029129. [DOI] [PubMed] [Google Scholar]
- Ruberte E., Marty T., Nellen D., Affolter M., Basler K. An absolute requirement for both the type II and type I receptors, punt and thick veins, for dpp signaling in vivo. Cell. 1995 Mar 24;80(6):889–897. doi: 10.1016/0092-8674(95)90292-9. [DOI] [PubMed] [Google Scholar]
- Sampath T. K., Rashka K. E., Doctor J. S., Tucker R. F., Hoffmann F. M. Drosophila transforming growth factor beta superfamily proteins induce endochondral bone formation in mammals. Proc Natl Acad Sci U S A. 1993 Jul 1;90(13):6004–6008. doi: 10.1073/pnas.90.13.6004. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Segal D., Gelbart W. M. Shortvein, a new component of the decapentaplegic gene complex in Drosophila melanogaster. Genetics. 1985 Jan;109(1):119–143. doi: 10.1093/genetics/109.1.119. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sekelsky J. J., Newfeld S. J., Raftery L. A., Chartoff E. H., Gelbart W. M. Genetic characterization and cloning of mothers against dpp, a gene required for decapentaplegic function in Drosophila melanogaster. Genetics. 1995 Mar;139(3):1347–1358. doi: 10.1093/genetics/139.3.1347. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Spencer F. A., Hoffmann F. M., Gelbart W. M. Decapentaplegic: a gene complex affecting morphogenesis in Drosophila melanogaster. Cell. 1982 Mar;28(3):451–461. doi: 10.1016/0092-8674(82)90199-4. [DOI] [PubMed] [Google Scholar]
- Sulston J. E., Albertson D. G., Thomson J. N. The Caenorhabditis elegans male: postembryonic development of nongonadal structures. Dev Biol. 1980 Aug;78(2):542–576. doi: 10.1016/0012-1606(80)90352-8. [DOI] [PubMed] [Google Scholar]
- Suzuki A., Thies R. S., Yamaji N., Song J. J., Wozney J. M., Murakami K., Ueno N. A truncated bone morphogenetic protein receptor affects dorsal-ventral patterning in the early Xenopus embryo. Proc Natl Acad Sci U S A. 1994 Oct 25;91(22):10255–10259. doi: 10.1073/pnas.91.22.10255. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Thomas J. H., Birnby D. A., Vowels J. J. Evidence for parallel processing of sensory information controlling dauer formation in Caenorhabditis elegans. Genetics. 1993 Aug;134(4):1105–1117. doi: 10.1093/genetics/134.4.1105. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Thomas J. H. Chemosensory regulation of development in C. elegans. Bioessays. 1993 Dec;15(12):791–797. doi: 10.1002/bies.950151204. [DOI] [PubMed] [Google Scholar]
- Trent C., Tsuing N., Horvitz H. R. Egg-laying defective mutants of the nematode Caenorhabditis elegans. Genetics. 1983 Aug;104(4):619–647. doi: 10.1093/genetics/104.4.619. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wilson R., Ainscough R., Anderson K., Baynes C., Berks M., Bonfield J., Burton J., Connell M., Copsey T., Cooper J. 2.2 Mb of contiguous nucleotide sequence from chromosome III of C. elegans. Nature. 1994 Mar 3;368(6466):32–38. doi: 10.1038/368032a0. [DOI] [PubMed] [Google Scholar]
- Wrana J. L., Attisano L., Cárcamo J., Zentella A., Doody J., Laiho M., Wang X. F., Massagué J. TGF beta signals through a heteromeric protein kinase receptor complex. Cell. 1992 Dec 11;71(6):1003–1014. doi: 10.1016/0092-8674(92)90395-s. [DOI] [PubMed] [Google Scholar]
- Wrana J. L., Attisano L., Wieser R., Ventura F., Massagué J. Mechanism of activation of the TGF-beta receptor. Nature. 1994 Aug 4;370(6488):341–347. doi: 10.1038/370341a0. [DOI] [PubMed] [Google Scholar]
- Xie T., Finelli A. L., Padgett R. W. The Drosophila saxophone gene: a serine-threonine kinase receptor of the TGF-beta superfamily. Science. 1994 Mar 25;263(5154):1756–1759. doi: 10.1126/science.8134837. [DOI] [PubMed] [Google Scholar]
- ten Dijke P., Yamashita H., Sampath T. K., Reddi A. H., Estevez M., Riddle D. L., Ichijo H., Heldin C. H., Miyazono K. Identification of type I receptors for osteogenic protein-1 and bone morphogenetic protein-4. J Biol Chem. 1994 Jun 24;269(25):16985–16988. [PubMed] [Google Scholar]