The signal transduction mechanisms underlying the pathophysiological activities of transforming growth factor-β (TGF-β) have been extensively studied since its discovery nearly 30 years ago. TGF-β ligands belong to a large superfamily of cytokines that bears its name (TGF-β Superfamily) and includes bone morphogenic proteins (1), activins (2), inhibin (3), growth/differentiation factors (4), Mullerian inhibiting substance (5), Nodal (6), and several other structurally-related polypeptides (7). Mammals express three TGF-β isoforms (i.e., TGF-β1, TGF-β2, and TGF-β3) that are encoded by distinct genes in a tissue-specific and developmentally-regulated manner (8). TGF-β was identified originally via its stimulation of morphological transformation and anchorage-independent growth in fibroblasts; however, this cytokine is now recognized as being a potent tumor suppressor that prevents the dysregulated growth and survival of epithelial, endothelial, and hematopoietic cells (8,9,10,11). In addition, numerous studies have clearly established TGF-β as a multifunctional cytokine that plays essential roles in regulating virtually all aspects of mammalian development and differentiation, and in maintaining mammalian tissue homeostasis (8,9,10,11). The pleiotropic nature of TGF-β is highlighted by the fact that every cell in the metazoan body can produce and respond to this cytokine. Even more remarkably, malignant cells have evolved a variety of complex mechanisms capable of circumventing the tumor suppressing activities of TGF-β, and in doing so, typically convert the functions of TGF-β to that of a tumor promoter, particularly the induction of carcinoma epithelial-mesenchymal transition, invasion, and dissemination to distant organ sites (8,9,10,11). This peculiar conversion in TGF-β function is known as the “ TGF-β Paradox,” which underlies the lethality of TGF-β in metastatic cancer cells. Thus, elucidating the effectors and signaling modules activated by TGF-β may offer new insights into the development of novel neoadjuvants capable of effectively targeting the TGF-β pathway to significantly improve the clinical course of patients with cancer, fibrosis, or immunologic disorders.
TGF-β is secreted from cells as a latent homodimeric polypeptide that becomes tethered to the extracellular matrix by latent-TGF-β-binding proteins. Mature TGF-β isoforms are activated and liberated from extracellular matrix depots by a variety of mechanisms, including proteolysis, reactive oxygen species, changes in pH, and physical interactions with integrins, thromobspondin-1, or SPARC (12,13,14,15). Once activated, mature TGF-β initiates transmembrane signaling by binding to two distinct transmembrane Ser/Thr protein kinases, termed TGF-β type I (TβR-I) and type II (TβR-II) receptors (16,17,18). In some cells and tissues, TGF-β also binds to a third cell surface receptor, TGF-β type III (TβR-III), which transfers TGF-β to TβR-II and TβR-I (19). Full activation of these cytokine:receptor ternary complexes transpires upon TβR-II-mediated transphosphorylation and activation of TβR-I (20,21), which then phosphorylates and activates the latent transcription factors, Smad2 and Smad3 (22,23). Afterward, phosphorylated Smad2/3 interact physically with Smad4, with the resulting heterotrimers translocating into the nucleus to regulate the expression of TGF-β-responsive genes (22,23). As depicted in Figure 1, these Smad-dependent events are subject to fine-tuning and crosstalk regulation in the cytoplasm by their interaction with a variety of adapter molecules, including SARA, Hgs, PML and Dab2 (24,25,26,27), and with Smad7 (28,29), whose inhibitory activity is modulated by STRAP, AMSH2, and Arkadia (30,31,32); and in the nucleus by their interaction with a variety of transcriptional activators and repressors that occur in a gene- and cell-specific manner (33). In addition to activating canonical Smad2/3-dependent signaling, accumulating evidence clearly links the development of a variety of human pathologies to aberrant coupling of TGF-β to its noncanonical effector molecules. Included in this ever expanding list of noncanonical signaling molecules stimulated by TGF-β are PI3K (34), AKT (35), mTOR (36), integrins (37) and focal adhesion kinase (38), and members of the MAP kinase (e.g., ERK1/2 (39), JNK (40), and p38 MAPK (41) small GTP-binding proteins (e.g., Ras, Rho, and Rac1) (11). The interactions and intersections between canonical and noncanonical TGF-β signaling systems are depicted in the pathway map.
1. Wozney JM. (1989) Bone morphogenetic proteins. Prog Growth Factor Res., 1(4):267-80.
2. Gaddy-Kurten D, Tsuchida K, Vale W. (1995) Activins and the receptor serine kinase superfamily. Recent Prog Horm Res., 50:109-29.
3. Bernard DJ, Chapman SC, Woodruff TK. (2001) Mechanisms of inhibin signal transduction. Recent Prog Horm Res., 56:417-50.
4. Rider CC, Mulloy B. (2010) Bone morphogenetic protein and growth differentiation factor cytokine families and their protein antagonists.Biochem J., 429(1):1-12.
5. Lee MM, Donahoe PK.(1993) Mullerian inhibiting substance: a gonadal hormone with multiple functions. Endocr Rev., 14(2):152-64.
6. Zhou X, Sasaki H, Lowe L, Hogan BL, Kuehn MR. (1993) Nodal is a novel TGF-beta-like gene expressed in the mouse node during gastrulation. Nature. 361(6412):543-7.
7. Herpin A, Lelong C, Favrel P. (2004) Transforming growth factor-beta-related proteins: an ancestral and widespread superfamily of cytokines in metazoans. Dev Comp Immunol., 28(5):461-85.
8. Blobe GC, Schiemann WP, Lodish HF. (2000) Role of transforming growth factor beta in human disease. N Engl J Med., 342(18):1350-1358.
9. Galliher AJ, Neil JR, Schiemann WP. (2006) Role of transforming growth factor-beta in cancer progression. Future Oncol., 2:743-763.
10. Schiemann WP. (2007) Targeted TGF-beta chemotherapies: friend or foe in treating human malignancies?. Expert Rev Anticancer Ther., 7:609-11.
11. Tian M, Schiemann WP. (2009) The TGF-beta paradox in human cancer: an update. Future Oncol., 5:259-271.
12. Schiemann BJ, Neil JR, Schiemann WP. (2003).SPARC inhibits epithelial cell proliferation in part through stimulation of the transforming growth factor-beta-signaling system. Mol Biol Cell., 14:3977-3988.
13. Annes JP, Munger JS, Rifkin DB. (2003). Making sense of latent TGFbeta activation. J Cell Sci., 116(Pt 2):217-224.
14. Bornstein P.(2009) Thrombospondins function as regulators of angiogenesis. J Cell Commun Signal., 3:189-200.
15. Sheppard D.(2005) Integrin-mediated activation of latent transforming growth factor beta. Cancer Metastasis Rev., 24:395-402.
16. Wrana JL, Attisano L, Cárcamo J, Zentella A, Doody J, Laiho M, Wang XF, Massagué J. (1992) TGF beta signals through a heteromeric protein kinase receptor complex. Cell., 71(6):1003-14.
17. Wieser R, Attisano L, Wrana JL, Massagué J. (1993) Signaling activity of transforming growth factor beta type II receptors lacking specific domains in the cytoplasmic region. Mol Cell Biol., 13(12):7239-47.
18. Lin HY, Moustakas A. (1994) TGF-beta receptors: structure and function. Cell Mol Biol (Noisy-le-grand)., 40(3):337-49.
19. Blobe GC, Schiemann WP, Pepin MC, Beauchemin M, Moustakas A, Lodish HF, O'Connor-McCourt MD. (2001) Functional roles for the cytoplasmic domain of the type III transforming growth factor beta receptor in regulating transforming growth factor beta signaling. J Biol Chem., 276(27):24627-37.
20. Wrana JL, Attisano L, Wieser R, Ventura F, Massagué J. (1994) Mechanism of activation of the TGF-beta receptor. Nature., 370:341-347.
21. Chen F, Weinberg RA. (1995) Biochemical evidence for the autophosphorylation and transphosphorylation of transforming growth factor beta receptor kinases. Proc Natl Acad Sci U S A., 92(5):1565-9.
22. Abdollah S, Macías-Silva M, Tsukazaki T, Hayashi H, Attisano L, Wrana JL. (1997) TbetaRI phosphorylation of Smad2 on Ser465 and Ser467 is required for Smad2-Smad4 complex formation and signaling. J Biol Chem., 272(44):27678-85.
23. Nakao A, Imamura T, Souchelnytskyi S, Kawabata M, Ishisaki A, Oeda E, Tamaki K, Hanai J, Heldin CH, Miyazono K, ten Dijke P. (1997) TGF-beta receptor-mediated signalling through Smad2, Smad3 and Smad4. EMBO J., 16(17):5353-62.
24. Tsukazaki, T., Chiang, T.A., Davison, A.F., Attisano, L., Wrana, J.L. (1998) SARA, a FYVE domain protein that recruits Smad2 to the TGFbeta receptor. Cell., 95(6):779-791.
25. Miura, S., Takeshita, T., Asao, H., Kimura, Y., Murata, K., Sasaki, Y., Hanai, J.I., Beppu, H., Tsukazaki, T., Wrana, J.L., Miyazono, K. and Sugamura, K. (2000) Hgs (Hrs), a FYVE domain protein, is involved in Smad signaling through cooperation with SARA. Mol Cell Biol., 20(24):9346-9355.
26. Lin, H.K., Bergmann, S. and Pandolfi, P.P. (2004) Cytoplasmic PML function in TGF-beta signalling. Nature., 431(7005):205-11.
27. Hocevar BA, Smine A, Xu XX, Howe PH. (2001) The adaptor molecule Disabled-2 links the transforming growth factor beta receptors to the Smad pathway. EMBO J., 20(11):2789-2801.
28. Hayashi H, Abdollah S, Qiu Y, Cai J, Xu YY, Grinnell BW, Richardson MA, Topper JN, Gimbrone MA Jr, Wrana JL, Falb D. (1997) The MAD-related protein Smad7 associates with the TGFbeta receptor and functions as an antagonist of TGFbeta signaling. Cell., 89(7):1165-1173.
29. Nakao A, Afrakhte M, Morén A, Nakayama T, Christian JL, Heuchel R, Itoh S, Kawabata M, Heldin NE, Heldin CH, ten Dijke P. (1997) Identification of Smad7, a TGFbeta-inducible antagonist of TGF-beta signalling. Nature. 389:631-635.
30. Datta PK, Moses HL. (2000) STRAP and Smad7 synergize in the inhibition of transforming growth factor beta signaling. Mol Cell Biol., 20(9):3157-3167.
31. Ibarrola N, Kratchmarova I, Nakajima D, Schiemann WP, Moustakas A, Pandey A, Mann M. (2004) Cloning of a novel signaling molecule, AMSH-2, that potentiates transforming growth factor beta signaling. BMC Cell Biol.,5:2.
32. Koinuma D, Shinozaki M, Komuro A, Goto K, Saitoh M, Hanyu A, Ebina M, Nukiwa T, Miyazawa K, Imamura T, Miyazono K. (2003) Arkadia amplifies TGF-beta superfamily signalling through degradation of Smad7. EMBO J., 22:6458-6470.
34. Yi JY, Shin I, Arteaga CL. (2005) Type I transforming growth factor beta receptor binds to and activates phosphatidylinositol 3-kinase. J Biol Chem., 280(11):10870-6.
35. Kato M, Putta S, Wang M, Yuan H, Lanting L, Nair I, Gunn A, Nakagawa Y, Shimano H, Todorov I, Rossi JJ, Natarajan R. (2009) TGF-beta activates Akt kinase through a microRNA-dependent amplifying circuit targeting PTEN. Nat Cell Biol., 11(7):881-9.
36. Lamouille S, Derynck R. (2007) Cell size and invasion in TGF-beta-induced epithelial to mesenchymal transition is regulated by activation of the mTOR pathway. J Cell Biol. 178(3):437-51.
37. Galliher AJ, Schiemann WP. (2006) Beta3 integrin and Src facilitate transforming growth factor-beta mediated induction of epithelial-mesenchymal transition in mammary epithelial cells. Breast Cancer Res., 8(4):R42.
38. Wendt MK, Schiemann WP. (2009) Therapeutic targeting of the focal adhesion complex prevents oncogenic TGF-beta signaling and metastasis. Breast Cancer Res. 11(5):R68.
39. Lee MK, Pardoux C, Hall MC, Lee PS, Warburton D, Qing J, Smith SM, Derynck R. (2007) TGF-beta activates Erk MAP kinase signalling through direct phosphorylation of ShcA. EMBO J. 26(17):3957-67.
40. Meriane M, Charrasse S, Comunale F, Gauthier-Rouvière C. (2002) Transforming growth factor beta activates Rac1 and Cdc42Hs GTPases and the JNK pathway in skeletal muscle cells. Biol Cell., 94(7-8):535-43.
41. Park JI, Lee MG, Cho K, Park BJ, Chae KS, Byun DS, Ryu BK, Park YK, Chi SG. (2003) Transforming growth factor-beta1 activates interleukin-6 expression in prostate cancer cells through the synergistic collaboration of the Smad2, p38-NF-kappaB, JNK, and Ras signaling pathways. Oncogene., 22(28):4314-32.