Downloaded from http://cshperspectives.cshlp.org/ on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press TGF-b and the TGF-b Family: Context-Dependent Roles in Cell and Tissue Physiology Masato Morikawa,1 Rik Derynck,2 and Kohei Miyazono3 1Ludwig Cancer Research, Science for Life Laboratory, Uppsala University, Biomedical Center, SE-751 24 Uppsala, Sweden 2Department of Cell and Tissue Biology, University of California at San Francisco, San Francisco, California 94143 3Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan Correspondence: [email protected] The transforming growth factor-b (TGF-b) is the prototype of the TGF-b family of growth and differentiation factors, which is encoded by 33 genes in mammals and comprises homo- and heterodimers. This review introduces the reader to the TGF-b family with its complexity of names and biological activities. It also introduces TGF-b as the best-studied factor among the TGF-b family proteins, with its diversity of roles in the control of cell proliferation and differentiation, wound healing and immune system, and its key roles in pathology, for exam- ple, skeletal diseases, fibrosis, and cancer. lthough initially thought to stimulate cell TGF-b has been well documented in most cell Aproliferation, just like many growth factors, types, and has been best characterized in epithe- it became rapidly accepted that transforming lial cells. The bifunctional and context-depen- growth factor b (TGF-b) is a bifunctional reg- dent nature of TGF-b activities was further con- ulator that either inhibits or stimulates cell pro- firmed in a large variety of cell systems and liferation. TGF-b was originally isolated as a biological responses. For example, TGF-b can cytokine that, together with epidermal growth inhibit EGF-dependent proliferation of cells factor (EGF), induces cellular transformation in monolayer culture, whereas TGF-b and and anchorage-independent growth of selected EGF synergistically enhance anchorage-inde- fibroblast cell lines (Roberts et al. 1981), yet did pendent growth of the same cells in soft agar not require the presence of EGF to induce phe- medium (Roberts et al. 1985). Now, it is widely notypic transformation of other fibroblast cell accepted that TGF-b regulates a variety of lines (Shipley et al. 1984). In contrast, TGF-b key events in normal development and physiol- was also identified as a growth inhibitor se- ogy, and perturbation of TGF-b signaling creted from confluent BSC-1 cells, epithelial has been implicated in the pathogenesis of dis- cells of African green monkey kidney (Tucker eases such as connective tissue disorders, fibro- et al. 1984). The growth inhibitory activity of sis, and cancer. Editors: Rik Derynck and Kohei Miyazono Additional Perspectives on The Biology of the TGF-b Family available at www.cshperspectives.org Copyright # 2016 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a021873 Cite this article as Cold Spring Harb Perspect Biol 2016;8:a021873 1 Downloaded from http://cshperspectives.cshlp.org/ on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press M. Morikawa et al. The identification of TGF-b family mem- 1995; Sekelsky et al. 1995). In C. elegans, daf-1 bers and their signaling components has en- and daf-4 turned out to also encode serine/thre- abled the characterization of the complex biol- onine transmembrane kinase receptors for ogy of the TGF-b family members. Molecular TGF-b family members. Screening for mutants cloning of TGF-b family members and their with similar phenotypes with daf-4 revealed signaling mediators started in 1985 with the re- three genes, sma-2, sma-3, and sma-4, that ported characterization of complementary DNA were structurally similar to Mad of Drosophila (cDNA) coding for human TGF-b1 (Derynck (Savage et al. 1996). In frog, mouse, and human, et al. 1985). Subsequently, various approaches, genes structurally similar to Mad and sma were based on biochemical purification, developmen- subsequently identified, and the designation tal genetics, and/or targeted cDNA cloning, led “Smad” (Sma and Mad) was adopted. Ligand to the identification of polypeptides structurally binding to specific tetrameric type II/type I re- similar to TGF-b1, which together comprise ceptor complexes stabilizes and activates their the members of the TGF-b family. Now signaling capacities, and the receptors then that the human and mouse genome sequence transduce the signals by phosphorylating car- projects are completed, it is apparent that mam- boxy-terminal serine residues of receptor-regu- malian genomes encode 33 TGF-b-related poly- lated (R-) Smads. In most cell types, TGF-bs and peptides. Table 1 shows the 33 known human activins induce phosphorylation of Smad2 TGF-b family polypeptides, which include three and Smad3 (activin/TGF-b-specific R-Smads), TGF-b isoforms, activins, nodal, bone morpho- and BMPs induce phosphorylation of Smad1, genetic proteins (BMPs), and growth and dif- Smad5, and Smad8 (BMP-specific R-Smads). ferentiation factors (GDFs). Although mostly The activated R-Smads form hetero-oligomeric studied as homodimers, various heterodimeric complexes with a common-partner (co-) Smad, combinations of these have also been identified that is, Smad4 in vertebrate cells (Lagna et al. and characterized as biologically active proteins. 1996; Zhang et al. 1996; Kawabata et al. 1998). In contrast to the large number of TGF-b The complexes translocate into the nucleus ligands, fewer receptors and downstream intra- where they regulate the expression of target cellular effectors, termed Smad proteins, medi- genes, such as those encoding inhibitory (I-) ate transduction of intracellular signaling. In Smads, namely, Smad6 and Smad7 in verte- 1991, a cDNA clone for an activin receptor, cur- brates, which can inhibit R-Smad activation by rently known as ActRII, was isolated (Mathews the receptors. Finally, TGF-b family proteins and Vale 1991). The kinase domain of this re- were also shown to induce PI3K-Akt signaling ceptor closely resembled the Caenorhabditis and to activate the common mitogen-associated elegans daf-1, a transmembrane serine/threo- protein (MAP) kinase pathways that are activat- nine-specific protein kinase, which at that time ed by receptor tyrosine kinases, albeit, generally, was seen as an orphan receptor, and provided the to a lower extent. Now that essential players in first indication that TGF-b family members sig- the signaling pathways have been identified, one nal through transmembrane serine/threonine of the major questions to be addressed in this kinases. In the following years, seven type I re- field is to reveal the precise molecular mecha- ceptors and five type II receptors were identified nisms that define the context-dependent dual in mammals and were shown to form hetero- roles of TGF-b family members. meric type I/type II receptorcomplexes.Genetic In this review, we will introduce the TGF-b analysis in Drosophila and C. elegans led to a family members, which in mammals are encod- breakthrough in how signals are transduced ed by 33 genes. Wewill cluster them into several from the receptors to the nucleus. In Drosophila, subgroups based on the structural or sequence mothers against dpp (Mad) was identified as a similarities of the encoded polypeptides. We gene encoding a component that acts epistati- further focus on the three TGF-b isoforms, cally downstream from Decapentaplegic (Dpp; TGF-b1, -b2, and -b3, as the best-studied fac- Drosophila BMP-2/-4 ligand) (Raftery et al. tors among the TGF-b family proteins. In ad- 2 Cite this article as Cold Spring Harb Perspect Biol 2016;8:a021873 Downloaded from http://cshperspectives.cshlp.org/ on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press Roles of TGF-b in Cell and Tissue Physiology Table 1. Names and genes for the TGF-b family proteins Official gene Protein name symbol (human) Protein name synonyms TGF-b1 TGFB1 CIF-A (cartilage-inducing factor-A), differentiation-inhibiting factor TGF-b2 TGFB2 G-TsF (glioblastoma-derived, T-cell suppressor factor), BSC-1 GI (BSC-1 cell-growth inhibitor), polyergin, CIF-B (cartilage- inducing factor-B) TGF-b3 TGFB3 Inhibin a INHA Inhibin A and Ba a,b Inhibin bA INHBA Inhibin A and activin A or AB, FRP (follicle-stimulating hormone-releasing protein), EDF (erythroid differentiation factor), XTC-MIF (Xenopus XTC cell mesoderm-inducing factor) a,b Inhibin bB INHBB Inhibin B and activin B or AB, XTC-MIF c Inhibin bC INHBC Activin C c Inhibin bE INHBE Activin E Nodal NODAL BMP-16 (bone morphogenetic protein-16) Myostatin MSTN GDF-8 (growth and differentiation factor-8) BMP-2 BMP2 BMP-3 BMP3 Osteogenin BMP-4 BMP4 BMP-2B BMP-5 BMP5 BMP-6 BMP6 Vgr1 (Vg1-related protein) BMP-7 BMP7 OP-1 (osteogenic protein-1) BMP-8A BMP8A OP-2 BMP-8B BMP8B OP-3 BMP-9 GDF2 GDF-2 BMP-10 BMP10 GDF-1 GDF1 GDF-3 GDF3 Vgr2 GDF-5 GDF5 CDMP-1 (cartilage-derived morphogenetic protein-1), BMP-14 GDF-6 GDF6 CDMP-2, BMP-13 GDF-7 GDF7 CDMP-3, BMP-12 GDF-9 GDF9 GDF-9B BMP15 BMP-15 GDF-10 GDF10 BMP-3b GDF-11 GDF11 BMP-11 GDF-15 GDF15 Placental TGF-b, placental BMP (PLAB), PDF (prostate-derived factor), NAG-1 (nonsteroidal anti-inflammatory drug-activated gene-1), MIC-1 (macrophage inhibitory cytokine-1) MIS (Mu¨llerian- AMH AMH (anti-Mu¨llerian hormone) inhibiting substance) Lefty A LEFTY2 EBAF (endometrial bleeding-associated factor), TGF-b4, Stra3 Lefty B LEFTY1 a Inhibin A or B is a heterodimer of inhibin a and inhibin bA or bB, respectively. b Activin A or B is a homodimer of inhibin bA or bB, respectively. Activin AB is a heterodimer of inhibin bA and bB.