Smad-dependent and Smad-independent pathways in TGF-β family signalling

Abstract

Transforming growth factor-β (TGF-β) proteins regulate cell function, and have key roles in development and carcinogenesis. The intracellular effectors of TGF-β signalling, the Smad proteins, are activated by receptors and translocate into the nucleus, where they regulate transcription. Although this pathway is inherently simple, combinatorial interactions in the heteromeric receptor and Smad complexes, receptor-interacting and Smad-interacting proteins, and cooperation with sequence-specific transcription factors allow substantial versatility and diversification of TGF-β family responses. Other signalling pathways further regulate Smad activation and function. In addition, TGF-β receptors activate Smad-independent pathways that not only regulate Smad signalling, but also allow Smad-independent TGF-β responses.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: General mechanism of TGF-β receptor and Smad activation.
Figure 2: Combinatorial interactions of type II and type I receptors define the signalling responses.
Figure 3: Structural organization and role of the domains of Smads, and candidate target sites for kinase pathways.
Figure 4: R-Smad activation is regulated by receptor-interacting proteins and Smad6/Smad7.
Figure 5: The R-Smad–Smad4 complex cooperates with sequence-specific transcription factors (X) that bind with high affinity to a cognate DNA sequence (XBE), yet also binds with lower affinity to a Smad-binding DNA element (SBE) to activate transcription in response to TGF-β ligand.
Figure 6: TGF-β receptor signalling through Smad-independent pathways.

References

  1. 1

    Massagué, J. How cells read TGF-β signals. Nature Rev. Mol. Cell Biol. 1, 169–178 (2000)

    Google Scholar 

  2. 2

    Itoh, S., Itoh, F., Goumans, M. J. & ten Dijke, P. Signaling of transforming growth factor-β family members through Smad proteins. Eur. J. Biochem. 267, 6954–6967 (2000)

    CAS  PubMed  PubMed Central  Google Scholar 

  3. 3

    Moustakas, A., Souchelnytskyi, S. & Heldin, C.-H. Smad regulation in TGF-β signal transduction. J. Cell Sci. 114, 4359–4369 (2001)

    CAS  PubMed  Google Scholar 

  4. 4

    Derynck, R. & Feng, X.-H. TGF-β receptor signaling. Biochim. Biophys. Acta 1333, F105–F150 (1997)

    CAS  PubMed  Google Scholar 

  5. 5

    Gilboa, L. et al. Bone morphogenetic protein receptor complexes on the surface of live cells: a new oligomerization mode for serine/threonine kinase receptors. Mol. Biol. Cell 11, 1023–1035 (2000)

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6

    Goumans, M. J. et al. Balancing the activation state of the endothelium via two distinct TGF-β type I receptors. EMBO J. 21, 1743–1753 (2002)

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7

    Miettinen, P. J., Ebner, R., Lopez, A. R. & Derynck, R. TGF-β induced transdifferentiation of mammary epithelial cells to mesenchymal cells: involvement of type I receptors. J. Cell Biol. 127, 2021–2036 (1994)

    CAS  PubMed  Google Scholar 

  8. 8

    Lai, Y. T. et al. Activin receptor-like kinase 2 can mediate atrioventricular cushion transformation. Dev. Biol. 222, 1–11 (2000)

    CAS  PubMed  Google Scholar 

  9. 9

    Yan, Y. T. et al. Dual roles of Cripto as a ligand and coreceptor in the nodal signaling pathway. Mol. Cell. Biol. 22, 4439–4449 (2002)

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10

    Blobe, G. C., Liu, X., Fang, S. J., How, T. & Lodish, H. F. A novel mechanism for regulating transforming growth factor β (TGF-β) signaling. Functional modulation of type III TGF-β receptor expression through interaction with the PDZ domain protein, GIPC. J. Biol. Chem. 276, 39608–39617 (2001)

    CAS  PubMed  Google Scholar 

  11. 11

    Barbara, N. P., Wrana, J. L. & Letarte, M. Endoglin is an accessory protein that interacts with the signaling receptor complex of multiple members of the transforming growth factor-β superfamily. J. Biol. Chem. 274, 584–594 (1999)

    CAS  PubMed  Google Scholar 

  12. 12

    Masuyama, N., Hanafusa, H., Kusakabe, M., Shibuya, H. & Nishida, E. Identification of two Smad4 proteins in Xenopus. Their common and distinct properties. J. Biol. Chem. 274, 12163–12170 (1999)

    CAS  PubMed  Google Scholar 

  13. 13

    Sirard, C. et al. Targeted disruption in murine cells reveals variable requirement for Smad4 in transforming growth factor β-related signaling. J. Biol. Chem. 275, 2063–2070 (2000)

    CAS  PubMed  Google Scholar 

  14. 14

    Durocher, D. et al. The molecular basis of FHA domain:phosphopeptide binding specificity and implications for phospho-dependent signaling mechanisms. Mol. Cell 6, 1169–1182 (2000)

    CAS  PubMed  Google Scholar 

  15. 15

    Choy, L., Skillington, J. & Derynck, R. Roles of autocrine TGF-β receptor and Smad signaling in adipocyte differentiation. J. Cell Biol. 149, 667–682 (2000)

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16

    Arora, K. & Warrior, R. A new Smurf in the village. Dev. Cell 1, 441–442 (2001)

    CAS  PubMed  Google Scholar 

  17. 17

    Zhu, H., Kavsak, P., Abdollah, S., Wrana, J. L. & Thomsen, G. H. A SMAD ubiquitin ligase targets the BMP pathway and affects embryonic pattern formation. Nature 400, 687–693 (1999)

    ADS  CAS  PubMed  Google Scholar 

  18. 18

    Zhang, Y., Chang, C., Gehling, D. J., Hemmati-Brivanlou, A. & Derynck, R. Regulation of Smad degradation and activity by Smurf2, an E3 ubiquitin ligase. Proc. Natl Acad. Sci. USA 98, 974–979 (2001)

    ADS  CAS  PubMed  Google Scholar 

  19. 19

    Bonni, S. et al. TGF-β induces assembly of a Smad2-Smurf2 ubiquitin ligase complex that targets SnoN for degradation. Nature Cell Biol. 3, 587–595 (2001)

    CAS  PubMed  Google Scholar 

  20. 20

    Lo, R. S. & Massagué, J. Ubiquitin-dependent degradation of TGF-β-activated Smad2. Nature Cell Biol. 1, 472–478 (1999)

    CAS  PubMed  Google Scholar 

  21. 21

    Fukuchi, M. et al. Ligand-dependent degradation of Smad3 by a ubiquitin ligase complex of ROC1 and associated proteins. Mol. Biol. Cell 12, 1431–1443 (2001)

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22

    Inman, G. J., Nicolas, F. J. & Hill, C. S. Nucleocytoplasmic shuttling of Smads 2, 3, and 4 permits sensing of TGF-β receptor activity. Mol. Cell 10, 283–294 (2002)

    CAS  PubMed  Google Scholar 

  23. 23

    Xu, L., Kang, Y., Col, S. & Massagué, J. Smad2 nucleocytoplasmic shuttling by nucleoporins CAN/Nup214 and Nup153 feeds TGF-β signaling complexes in the cytoplasm and nucleus. Mol. Cell 10, 271–282 (2002)

    CAS  PubMed  Google Scholar 

  24. 24

    Lee, P. S., Chang, C., Liu, D. & Derynck, R. Sumoylation of Smad4, the common Smad mediator of TGF-β family signaling. J. Biol. Chem. 278, 27853–27863 (2003)

    CAS  PubMed  Google Scholar 

  25. 25

    Xu, J. & Attisano, L. Mutations in the tumor suppressors Smad2 and Smad4 inactivate transforming growth factor β signaling by targeting Smads to the ubiquitin-proteasome pathway. Proc. Natl Acad. Sci. USA 97, 4820–4825 (2000)

    ADS  CAS  PubMed  Google Scholar 

  26. 26

    Wan, M. et al. Jab1 antagonizes TGF-β signaling by inducing Smad4 degradation. EMBO Rep. 3, 171–176 (2002)

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27

    Huse, M. et al. The TGF-β receptor activation process: an inhibitor- to substrate-binding switch. Mol. Cell 8, 671–682 (2001)

    CAS  Google Scholar 

  28. 28

    Penheiter, S. G. et al. Internalization-dependent and -independent requirements for transforming growth factor β receptor signaling via the Smad pathway. Mol. Cell. Biol. 22, 4750–4759 (2002)

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29

    Hayes, S., Chawla, A. & Corvera, S. TGF-β receptor internalization into EEA1-enriched early endosomes: role in signaling to Smad2. J. Cell Biol. 158, 1239–1249 (2002)

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30

    Di Guglielmo, G. M., Le Roy, C., Goodfellow, A. F. & Wrana, J. L. Distinct endocytic pathways regulate TGF-b receptor signaling and turnover. Nature Cell Biol. 5, 410–421 (2003)

    CAS  PubMed  Google Scholar 

  31. 31

    Hocevar, B. A., Smine, A., Xu, X. X. & Howe, P. H. The adaptor molecule Disabled-2 links the transforming growth factor β receptors to the Smad pathway. EMBO J. 20, 2789–2801 (2001)

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32

    Razani, B. et al. Caveolin-1 regulates transforming growth factor (TGF)-β/SMAD signaling through an interaction with the TGF-β type I receptor. J. Biol. Chem. 276, 6727–6738 (2001)

    CAS  PubMed  Google Scholar 

  33. 33

    Dong, C., Li, Z., Alvarez, R. Jr, Feng, X.-H. & Goldschmidt-Clermont, P. J. Microtubule binding to Smads may regulate TGF-β activity. Mol. Cell 5, 27–34 (2000)

    CAS  PubMed  Google Scholar 

  34. 34

    Sasaki, A., Masuda, Y., Ohta, Y., Ikeda, K. & Watanabe, K. Filamin associates with Smads and regulates transforming growth factor-β signaling. J. Biol. Chem. 276, 17871–17877 (2001)

    CAS  PubMed  Google Scholar 

  35. 35

    Tang, Y. et al. Disruption of transforming growth factor-β signaling in ELF β-spectrin-deficient mice. Science 299, 574–577 (2003)

    ADS  CAS  Google Scholar 

  36. 36

    Kavsak, P. et al. Smad7 binds to Smurf2 to form an E3 ubiquitin ligase that targets the TGF-β receptor for degradation. Mol. Cell 6, 1365–1375 (2000)

    CAS  PubMed  Google Scholar 

  37. 37

    Ebisawa, T. et al. Smurf1 interacts with transforming growth factor-β type I receptor through Smad7 and induces receptor degradation. J. Biol. Chem. 276, 12477–12480 (2001)

    CAS  PubMed  Google Scholar 

  38. 38

    Wu, J. W. et al. Crystal structure of a phosphorylated Smad2. Recognition of phosphoserine by the MH2 domain and insights on Smad function in TGF-β signaling. Mol. Cell 8, 1277–1289 (2001)

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39

    Chacko, B. M. et al. The L3 loop and C-terminal phosphorylation jointly define Smad protein trimerization. Nature Struct. Biol. 8, 248–253 (2001)

    CAS  PubMed  Google Scholar 

  40. 40

    Inman, G. J. & Hill, C. S. Stoichiometry of active Smad-transcription factor complexes on DNA. J. Biol. Chem. 277, 51008–51016 (2002)

    CAS  PubMed  Google Scholar 

  41. 41

    Feng, X.-H., Lin, X. & Derynck, R. Smad2 Smad3 and Smad4 cooperate with Sp1 to induce p15Ink4B transcription in response to TGF-β. EMBO J. 19, 5178–5193 (2000)

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42

    Watanabe, M., Masuyama, N., Fukuda, M. & Nishida, E. Regulation of intracellular dynamics of Smad4 by its leucine-rich nuclear export signal. EMBO Rep. 1, 176–182 (2000)

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43

    Xiao, Z., Watson, N., Rodriguez, C. & Lodish, H. F. Nucleocytoplasmic shuttling of Smad1 conferred by its nuclear localization and nuclear export signals. J. Biol. Chem. 276, 39404–39410 (2001)

    CAS  PubMed  Google Scholar 

  44. 44

    Xu, L., Chen, Y.-G. & Massagué, J. The nuclear import function of Smad2 is masked by SARA and unmasked by TGFβ-dependent phosphorylation. Nature Cell Biol. 2, 559–562 (2000)

    CAS  PubMed  Google Scholar 

  45. 45

    Kurisaki, A., Kose, S., Yoneda, Y., Heldin, C. H. & Moustakas, A. Transforming growth factor-β induces nuclear import of Smad3 in an importin-β1 and Ran-dependent manner. Mol. Biol. Cell 12, 1079–1091 (2001)

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46

    Itoh, F. et al. Promoting bone morphogenetic protein signaling through negative regulation of inhibitory Smads. EMBO J. 20, 4132–4142 (2001)

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47

    Hanyu, A. et al. The N domain of Smad7 is essential for specific inhibition of transforming growth factor-β signaling. J. Cell Biol. 155, 1017–1027 (2001)

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48

    Bai, S. & Cao, X. A nuclear antagonistic mechanism of inhibitory Smads in transforming growth factor-β signaling. J. Biol. Chem. 277, 4176–4182 (2002)

    CAS  PubMed  Google Scholar 

  49. 49

    Pulaski, L., Landström, M., Heldin, C. H. & Souchelnytskyi, S. Phosphorylation of Smad7 at Ser-249 does not interfere with its inhibitory role in transforming growth factor-β-dependent signaling but affects Smad7-dependent transcriptional activation. J. Biol. Chem. 276, 14344–14349 (2001)

    CAS  PubMed  Google Scholar 

  50. 50

    Grönroos, E., Hellman, U., Heldin, C. H. & Ericsson, J. Control of Smad7 stability by Competition between acetylation and ubiquitination. Mol. Cell 10, 483–493 (2002)

    PubMed  PubMed Central  Google Scholar 

  51. 51

    de Caestecker, M. P. et al. Smad2 transduces common signals from receptor serine-threonine and tyrosine kinases. Genes Dev. 12, 1587–1592 (1998)

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52

    Kretzschmar, M., Doody, J., Timokhina, I. & Massagué, J. A mechanism of repression of TGF-β/Smad signaling by oncogenic Ras. Genes Dev. 13, 804–816 (1999)

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53

    Funaba, M., Zimmerman, C. M. & Mathews, L. S. Modulation of Smad2-mediated signaling by extracellular signal-regulated kinase. J. Biol. Chem. 277, 41361–41368 (2002)

    CAS  PubMed  Google Scholar 

  54. 54

    Engel, M. E., McDonnell, M. A., Law, B. K. & Moses, H. L. Interdependent SMAD and JNK signaling in transforming growth factor-β-mediated transcription. J. Biol. Chem. 274, 37413–37420 (1999)

    CAS  Google Scholar 

  55. 55

    Janda, E. et al. Ras and TGF-β cooperatively regulate epithelial cell plasticity and metastasis: dissection of Ras signaling pathways. J. Cell Biol. 156, 299–313 (2002)

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56

    Grimm, O. H. & Gurdon, J. B. Nuclear exclusion of Smad2 is a mechanism leading to loss of competence. Nature Cell Biol. 4, 519–522 (2002)

    CAS  PubMed  Google Scholar 

  57. 57

    Brown, J. D., DiChiara, M. R., Anderson, K. R., Gimbrone, M. A. Jr & Topper, J. N. MEKK-1, a component of the stress (stress-activated protein kinase/c-Jun N-terminal kinase) pathway, can selectively activate Smad2-mediated transcriptional activation in endothelial cells. J. Biol. Chem. 274, 8797–8805 (1999)

    CAS  Google Scholar 

  58. 58

    Wicks, S. J., Lui, S., Abdel-Wahab, N., Mason, R. M. & Chantry, A. Inactivation of smad-transforming growth factor β signaling by Ca2+-calmodulin-dependent protein kinase II. Mol. Cell. Biol. 20, 8103–8111 (2000)

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 59

    Yakymovych, I., ten Dijke, P., Heldin, C. H. & Souchelnytskyi, S. Regulation of Smad signaling by protein kinase C. FASEB J. 15, 553–555 (2001)

    CAS  PubMed  Google Scholar 

  60. 60

    Chen, C.-R., Kang, Y., Siegel, P. M. & Massagué, J. E2F4/5 and p107 as Smad cofactors linking the TGFβ receptor to c-myc repression. Cell 110, 19–32 (2002)

    CAS  PubMed  Google Scholar 

  61. 61

    Kang, Y., Chen, C.-R. & Massagué, J. A self-enabling TGF-β response coupled to stress signaling: Smad engages stress response factor ATF3 for Id1 repression in epithelial cells. Mol. Cell 11, 915–926 (2003)

    CAS  PubMed  Google Scholar 

  62. 62

    Comijn, J. et al. The two-handed E box binding zinc finger protein SIP1 downregulates E-cadherin and induces invasion. Mol. Cell 7, 1267–1278 (2001)

    CAS  PubMed  Google Scholar 

  63. 63

    Alliston, T., Choy, L., Ducy, P., Karsenty, G. & Derynck, R. TGF-β-induced repression of CBFA1 by Smad3 decreases cbfa1 and osteocalcin expression and inhibits osteoblast differentiation. EMBO J. 20, 2254–2272 (2001)

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64

    Liu, D., Black, B. L. & Derynck, R. TGF-β inhibits muscle differentiation through functional repression of myogenic transcription factors by Smad3. Genes Dev. 15, 2950–2966 (2001)

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65

    Choy, L. & Derynck, R. Transforming growth factor-β inhibits adipocyte differentiation by Smad3 interacting with CCAAT/enhancer-binding protein (C/EBP) and repressing C/EBP transactivation function. J. Biol. Chem. 278, 9609–9619 (2003)

    CAS  PubMed  Google Scholar 

  66. 66

    Liberati, N. T., Moniwa, M., Borton, A. J., Davie, J. R. & Wang, X.-F. An essential role for Mad homology domain 1 in the association of Smad3 with histone deacetylase activity. J. Biol. Chem. 276, 22595–22603 (2001)

    CAS  PubMed  Google Scholar 

  67. 67

    Choy, L. & Derynck, R. The type II transforming growth factor (TGF)-β receptor-interacting protein TRIP-1 acts as a modulator of the TGF-β response. J. Biol. Chem. 273, 31455–31462 (1998)

    CAS  PubMed  Google Scholar 

  68. 68

    McGonigle, S., Beall, M. J. & Pearce, E. J. Eukaryotic initiation factor 2 α subunit associates with TGF-β receptors and 14-3-3ε and acts as a modulator of the TGF-β response. Biochemistry 41, 579–587 (2002)

    CAS  PubMed  Google Scholar 

  69. 69

    Griswold-Prenner, I., Kamibayashi, C., Maruoka, E. M., Mumby, M. C. & Derynck, R. Physical and functional interactions between type I transforming growth factor β receptors and Bα, a WD-40 repeat subunit of phosphatase 2A. Mol. Cell. Biol. 18, 6595–6604 (1998)

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70

    Datta, P. K. & Moses, H. L. STRAP and Smad7 synergize in the inhibition of transforming growth factor β signaling. Mol. Cell. Biol. 20, 3157–3167 (2000)

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 71

    Huse, M., Chen, Y.-G., Massagué, J. & Kuriyan, J. Crystal structure of the cytoplasmic domain of the type I TGF-β receptor in complex with FKBP12. Cell 96, 425–436 (1999)

    CAS  PubMed  Google Scholar 

  72. 72

    Yao, D., Doré, J. J. Jr & Leof, E. B. FKBP12 is a negative regulator of transforming growth factor-β receptor internalization. J. Biol. Chem. 275, 13149–13154 (2000)

    CAS  PubMed  Google Scholar 

  73. 73

    Aghdasi, B. et al. FKBP12, the 12-kDa FK506-binding protein, is a physiologic regulator of the cell cycle. Proc. Natl Acad. Sci. USA 98, 2425–2430 (2001)

    ADS  CAS  PubMed  Google Scholar 

  74. 74

    Ventura, F., Liu, F., Doody, J. & Massagué, J. Interaction of transforming growth factor-β receptor I with farnesyl-protein transferase-α in yeast and mammalian cells. J. Biol. Chem. 271, 13931–13934 (1996)

    CAS  PubMed  Google Scholar 

  75. 75

    Yu, L., Hebert, M. C. & Zhang, Y. E. TGF-β receptor-activated p38 MAP kinase mediates Smad-independent TGF-β responses. EMBO J. 21, 3749–3759 (2002)

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76

    Yue, J. & Mulder, K. M. Activation of the mitogen-activated protein kinase pathway by transforming growth factor-β. Methods Mol. Biol. 142, 125–131 (2000)

    CAS  PubMed  Google Scholar 

  77. 77

    Yamaguchi, K. et al. XIAP, a cellular member of the inhibitor of apoptosis protein family, links the receptors to TAB1–TAK1 in the BMP signaling pathway. EMBO J. 18, 179–187 (1999)

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78

    Salvesen, G. S. & Duckett, C. S. IAP proteins: blocking the road to death's door. Nature Rev. Mol. Cell Biol. 3, 401–410 (2002)

    CAS  Google Scholar 

  79. 79

    Bakin, A. V., Rinehart, C., Tomlinson, A. K. & Arteaga, C. L. p38 mitogen-activated protein kinase is required for TGFβ-mediated fibroblastic transdifferentiation and cell migration. J. Cell Sci. 115, 3193–3206 (2002)

    CAS  PubMed  Google Scholar 

  80. 80

    Zavadil, J. et al. Genetic programs of epithelial cell plasticity directed by transforming growth factor-β. Proc. Natl Acad. Sci. USA 98, 6686–6691 (2001)

    ADS  CAS  PubMed  Google Scholar 

  81. 81

    Kimura, N., Matsuo, R., Shibuya, H., Nakashima, K. & Taga, T. BMP2-induced apoptosis is mediated by activation of the TAK1-p38 kinase pathway that is negatively regulated by Smad6. J. Biol. Chem. 275, 17647–17652 (2000)

    CAS  PubMed  Google Scholar 

  82. 82

    Mazars, A. et al. Evidence for a role of the JNK cascade in Smad7-mediated apoptosis. J. Biol. Chem. 276, 36797–36803 (2001)

    CAS  PubMed  Google Scholar 

  83. 83

    Pessah, M. et al. c-Jun associates with the oncoprotein Ski and suppresses Smad2 transcriptional activity. J. Biol. Chem. 277, 29094–29100 (2002)

    CAS  PubMed  Google Scholar 

  84. 84

    Bhowmick, N. A. et al. Transforming growth factor-β1 mediates epithelial to mesenchymal transdifferentiation through a RhoA-dependent mechanism. Mol. Biol. Cell 12, 27–36 (2001)

    CAS  PubMed  PubMed Central  Google Scholar 

  85. 85

    Edlund, S., Landström, M., Heldin, C. H. & Aspenström, P. Transforming growth factor-β-induced mobilization of actin cytoskeleton requires signaling by small GTPases Cdc42 and RhoA. Mol. Biol. Cell 13, 902–914 (2002)

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86

    Engel, M. E., Datta, P. K. & Moses, H. L. RhoB is stabilized by transforming growth factor β and antagonizes transcriptional activation. J. Biol. Chem. 273, 9921–9926 (1998)

    CAS  PubMed  Google Scholar 

  87. 87

    Shen, X. et al. The activity of guanine exchange factor NET1 is essential for transforming growth factor-β-mediated stress fiber formation. J. Biol. Chem. 276, 15362–15368 (2001)

    CAS  PubMed  Google Scholar 

  88. 88

    Bishop, A. L. & Hall, A. Rho GTPases and their effector proteins. Biochem. J. 348, 241–255 (2000)

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89

    Bakin, A. V., Tomlinson, A. K., Bhowmick, N. A., Moses, H. L. & Arteaga, C. L. Phosphatidylinositol 3-kinase function is required for transforming growth factor β-mediated epithelial to mesenchymal transition and cell migration. J. Biol. Chem. 275, 36803–36810 (2000)

    CAS  PubMed  Google Scholar 

  90. 90

    Vinals, F. & Pouysségur, J. Transforming growth factor β1 (TGF-β1) promotes endothelial cell survival during in vitro angiogenesis via an autocrine mechanism implicating TGF-α signaling. Mol. Cell. Biol. 21, 7218–7230 (2001)

    CAS  PubMed  PubMed Central  Google Scholar 

  91. 91

    Piek, E., Moustakas, A., Kurisaki, A., Heldin, C. H. & ten Dijke, P. TGF-β type I receptor/ALK-5 and Smad proteins mediate epithelial to mesenchymal transdifferentiation in NMuMG breast epithelial cells. J. Cell Sci. 112, 4557–4568 (1999)

    CAS  PubMed  Google Scholar 

  92. 92

    Petritsch, C., Beug, H., Balmain, A. & Oft, M. TGF-β inhibits p70 S6 kinase via protein phosphatase 2A to induce G1 arrest. Genes Dev. 14, 3093–3101 (2000)

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93

    Bennett, D. & Alphey, L. PP1 binds Sara and negatively regulates Dpp signalling in Drosophila melanogaster. Nature Genet. 31, 419–423 (2002)

    CAS  PubMed  Google Scholar 

  94. 94

    Stroschein, S. L., Bonni, S., Wrana, J. L. & Luo, K. Smad3 recruits the anaphase-promoting complex for ubiquitination and degradation of SnoN. Genes Dev. 15, 2822–2836 (2001)

    CAS  PubMed  PubMed Central  Google Scholar 

  95. 95

    Wan, Y., Liu, X. & Kirschner, M. W. The anaphase-promoting complex mediates TGF-β signaling by targeting SnoN for destruction. Mol. Cell 8, 1027–1039 (2001)

    CAS  PubMed  Google Scholar 

  96. 96

    Yamakawa, N., Tsuchida, K. & Sugino, H. The rasGAP-binding protein, Dok-1, mediates activin signaling via serine/threonine kinase receptors. EMBO J. 21, 1684–1694 (2002)

    CAS  PubMed  PubMed Central  Google Scholar 

  97. 97

    Bai, R. Y. et al. SMIF, a Smad4-interacting protein that functions as a co-activator in TGFβ signalling. Nature Cell Biol. 4, 181–190 (2002)

    CAS  PubMed  Google Scholar 

  98. 98

    Kato, Y., Habas, R., Katsuyama, Y., Naar, A. M. & He, X. A component of the ARC/Mediator complex required for TGF-β/Nodal signalling. Nature 418, 641–646 (2002)

    ADS  CAS  PubMed  Google Scholar 

  99. 99

    Seoane, J. et al. TGF-β influences Myc, Miz-1 and Smad to control the CDK inhibitor p15INK4b. Nature Cell Biol. 3, 400–408 (2001)

    CAS  PubMed  Google Scholar 

  100. 100

    Feng, X. H., Liang, Y. Y., Liang, M., Zhai, W. & Lin, X. Direct interaction of c-Myc with Smad2 and Smad3 to inhibit TGF-β-mediated induction of the CDK inhibitor p15Ink4B. Mol. Cell 9, 133–143 (2002)

    CAS  Google Scholar 

  101. 101

    Foletta, V. C. et al. Direct signaling by the BMP type II receptor via the cytoskeletal regulator LIMK1. J. Cell Biol. 162, 1089–1098 (2003)

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We apologize to the many researchers whose work could not be cited because of space limitations or was only cited indirectly by referring to reviews or more recent papers.

Author information

Affiliations

Authors

Corresponding authors

Correspondence to Rik Derynck or Ying E. Zhang.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Derynck, R., Zhang, Y. Smad-dependent and Smad-independent pathways in TGF-β family signalling. Nature 425, 577–584 (2003). https://doi.org/10.1038/nature02006

Download citation

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing