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PMID: 12110587 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

TGF-beta receptor-activated p38 MAP kinase mediates Smad-independent TGF-beta responses.

The EMBO journal ·Vol. 21 ·No. 14 ·2002-07-15 ·Pages 3749-59

Yu L, Hébert MC, Zhang YE

Abstract

Through the action of its membrane-bound type I receptors, transforming growth factor-beta (TGF-beta) elicits a wide range of cellular responses that regulate cell proliferation, differentiation and apoptosis. Many of the signaling responses induced by TGF-beta are mediated by Smad proteins, but certain evidence has suggested that TGF-beta can also signal independently of Smads. We found in mouse mammary epithelial (NMuMG) cells, which respond to TGF-beta treatment in multiple ways, that TGF-beta-induced activation of p38 MAP kinase is required for TGF-beta-induced apoptosis, epithelial-to-mesenchymal transition (EMT), but not growth arrest. We further demonstrated that activation of p38 is independent of Smads using a mutant type I receptor, which is incapable of activating Smads but still retains the kinase activity. This mutant receptor is sufficient to activate p38 and cause NMuMG cells to undergo apoptosis. However, it is not sufficient to induce EMT. These results indicate that TGF-beta receptor signals through multiple intracellular pathways and provide first-hand biochemical evidence for the existence of Smad-independent TGF-beta receptor signaling.

MeSH Terms
Animals Apoptosis/physiology Cell Division/physiology Cell Line DNA-Binding Proteins/metabolism Enzyme Activation Mice Mitogen-Activated Protein Kinases/metabolism Receptors, Transforming Growth Factor beta/metabolism Smad Proteins Trans-Activators/metabolism Transforming Growth Factor beta/metabolism,physiology p38 Mitogen-Activated Protein Kinases
Chemicals
DNA-Binding Proteins Receptors, Transforming Growth Factor beta Smad Proteins Trans-Activators Transforming Growth Factor beta Mitogen-Activated Protein Kinases p38 Mitogen-Activated Protein Kinases
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Yu Li
Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
Hébert Mindy C
Zhang Ying E
References (58)
58 references, click to expand
  1. Regulation of Smad activity.
    Cell. 2000 Jan 21;100(2):189-92 PMID: 10660041
  2. TGF-beta1 and Ha-Ras collaborate in modulating the phenotypic plasticity and invasiveness of epithelial tumor cells.
    Genes Dev. 1996 Oct 1;10(19):2462-77 PMID: 8843198
  3. The p38 signal transduction pathway: activation and function.
    Cell Signal. 2000 Jan;12(1):1-13 PMID: 10676842
  4. Characterization of a bone morphogenetic protein-responsive Smad-binding element.
    Mol Biol Cell. 2000 Feb;11(2):555-65 PMID: 10679014
  5. Roles of autocrine TGF-beta receptor and Smad signaling in adipocyte differentiation.
    J Cell Biol. 2000 May 1;149(3):667-82 PMID: 10791980
  6. Smad7 mediates apoptosis induced by transforming growth factor beta in prostatic carcinoma cells.
    Curr Biol. 2000 May 4;10(9):535-8 PMID: 10801443
  7. Endogenous patterns of TGFbeta superfamily signaling during early Xenopus development.
    Development. 2000 Jul;127(13):2917-31 PMID: 10851136
  8. Wnt signaling: Moving in a new direction.
    Curr Biol. 2000 Jul 27-Aug 10;10(15):R562-4 PMID: 10959830
  9. Role of Smad proteins and transcription factor Sp1 in p21(Waf1/Cip1) regulation by transforming growth factor-beta.
    J Biol Chem. 2000 Sep 22;275(38):29244-56 PMID: 10878024
  10. Raf induces TGFbeta production while blocking its apoptotic but not invasive responses: a mechanism leading to increased malignancy in epithelial cells.
    Genes Dev. 2000 Oct 15;14(20):2610-22 PMID: 11040215
  11. Signaling networks: the origins of cellular multitasking.
    Cell. 2000 Oct 13;103(2):193-200 PMID: 11057893
  12. Signal transduction by the JNK group of MAP kinases.
    Cell. 2000 Oct 13;103(2):239-52 PMID: 11057897
  13. A transcriptional partner for MAD proteins in TGF-beta signalling.
    Nature. 1996 Oct 24;383(6602):691-6 PMID: 8878477
  14. The MAD-related protein Smad7 associates with the TGFbeta receptor and functions as an antagonist of TGFbeta signaling.
    Cell. 1997 Jun 27;89(7):1165-73 PMID: 9215638
  15. A kinase subdomain of transforming growth factor-beta (TGF-beta) type I receptor determines the TGF-beta intracellular signaling specificity.
    EMBO J. 1997 Jul 1;16(13):3912-23 PMID: 9233801
  16. MEK kinases are regulated by EGF and selectively interact with Rac/Cdc42.
    EMBO J. 1997 Aug 15;16(16):4961-72 PMID: 9305638
  17. Identification of Smad7, a TGFbeta-inducible antagonist of TGF-beta signalling.
    Nature. 1997 Oct 9;389(6651):631-5 PMID: 9335507
  18. Human Smad3 and Smad4 are sequence-specific transcription activators.
    Mol Cell. 1998 Mar;1(4):611-7 PMID: 9660945
  19. Determinants of specificity in TGF-beta signal transduction.
    Genes Dev. 1998 Jul 15;12(14):2144-52 PMID: 9679059
  20. Smads and early developmental signaling by the TGFbeta superfamily.
    Genes Dev. 1998 Aug 15;12(16):2445-62 PMID: 9716398
  21. TGF-beta signal transduction.
    Annu Rev Biochem. 1998;67:753-91 PMID: 9759503
  22. The type II transforming growth factor (TGF)-beta receptor-interacting protein TRIP-1 acts as a modulator of the TGF-beta response.
    J Biol Chem. 1998 Nov 20;273(47):31455-62 PMID: 9813058
  23. TGF-beta induces fibronectin synthesis through a c-Jun N-terminal kinase-dependent, Smad4-independent pathway.
    EMBO J. 1999 Mar 1;18(5):1345-56 PMID: 10064600
  24. ATF-2 is a common nuclear target of Smad and TAK1 pathways in transforming growth factor-beta signaling.
    J Biol Chem. 1999 Mar 26;274(13):8949-57 PMID: 10085140
  25. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor.
    Cell. 1999 Mar 19;96(6):857-68 PMID: 10102273
  26. Regulation of Smad signalling by protein associations and signalling crosstalk.
    Trends Cell Biol. 1999 Jul;9(7):274-9 PMID: 10370243
  27. Involvement of the p38 mitogen-activated protein kinase pathway in transforming growth factor-beta-induced gene expression.
    J Biol Chem. 1999 Sep 17;274(38):27161-7 PMID: 10480932
  28. Epithelial cell plasticity in development and tumor progression.
    Cancer Metastasis Rev. 1999;18(1):31-42 PMID: 10505544
  29. Smad2, Smad3 and Smad4 cooperate with Sp1 to induce p15(Ink4B) transcription in response to TGF-beta.
    EMBO J. 2000 Oct 2;19(19):5178-93 PMID: 11013220
  30. Phosphatidylinositol 3-kinase function is required for transforming growth factor beta-mediated epithelial to mesenchymal transition and cell migration.
    J Biol Chem. 2000 Nov 24;275(47):36803-10 PMID: 10969078
  31. Transforming growth factor-beta1 mediates epithelial to mesenchymal transdifferentiation through a RhoA-dependent mechanism.
    Mol Biol Cell. 2001 Jan;12(1):27-36 PMID: 11160820
  32. Defective repression of c-myc in breast cancer cells: A loss at the core of the transforming growth factor beta growth arrest program.
    Proc Natl Acad Sci U S A. 2001 Jan 30;98(3):992-9 PMID: 11158583
  33. How cells read TGF-beta signals.
    Nat Rev Mol Cell Biol. 2000 Dec;1(3):169-78 PMID: 11252892
  34. TGFbeta influences Myc, Miz-1 and Smad to control the CDK inhibitor p15INK4b.
    Nat Cell Biol. 2001 Apr;3(4):400-8 PMID: 11283614
  35. TGF-beta-induced apoptosis is mediated by the adapter protein Daxx that facilitates JNK activation.
    Nat Cell Biol. 2001 Aug;3(8):708-14 PMID: 11483955
  36. Evidence for a role of the JNK cascade in Smad7-mediated apoptosis.
    J Biol Chem. 2001 Sep 28;276(39):36797-803 PMID: 11477069
  37. TGF-beta signaling in tumor suppression and cancer progression.
    Nat Genet. 2001 Oct;29(2):117-29 PMID: 11586292
  38. TGF-(beta) type I receptor/ALK-5 and Smad proteins mediate epithelial to mesenchymal transdifferentiation in NMuMG breast epithelial cells.
    J Cell Sci. 1999 Dec;112 ( Pt 24):4557-68 PMID: 10574705
  39. Interdependent SMAD and JNK signaling in transforming growth factor-beta-mediated transcription.
    J Biol Chem. 1999 Dec 24;274(52):37413-20 PMID: 10601313
  40. Signaling--2000 and beyond.
    Cell. 2000 Jan 7;100(1):113-27 PMID: 10647936
  41. Transforming growth factor beta enhances epithelial cell survival via Akt-dependent regulation of FKHRL1.
    Mol Biol Cell. 2001 Nov;12(11):3328-39 PMID: 11694570
  42. Integrin beta 1 signaling is necessary for transforming growth factor-beta activation of p38MAPK and epithelial plasticity.
    J Biol Chem. 2001 Dec 14;276(50):46707-13 PMID: 11590169
  43. c-myc is a downstream target of the Smad pathway.
    J Biol Chem. 2002 Jan 4;277(1):854-61 PMID: 11689553
  44. TGF-beta signaling: positive and negative effects on tumorigenesis.
    Curr Opin Genet Dev. 2002 Feb;12(1):22-9 PMID: 11790550
  45. TGF beta signals through a heteromeric protein kinase receptor complex.
    Cell. 1992 Dec 11;71(6):1003-14 PMID: 1333888
  46. Targeting expression of a transforming growth factor beta 1 transgene to the pregnant mammary gland inhibits alveolar development and lactation.
    EMBO J. 1993 May;12(5):1835-45 PMID: 8491177
  47. The novel primary response gene MyD118 and the proto-oncogenes myb, myc, and bcl-2 modulate transforming growth factor beta 1-induced apoptosis of myeloid leukemia cells.
    Mol Cell Biol. 1994 Apr;14(4):2352-60 PMID: 8139540
  48. Type I receptors specify growth-inhibitory and transcriptional responses to transforming growth factor beta and activin.
    Mol Cell Biol. 1994 Jun;14(6):3810-21 PMID: 8196624
  49. p15INK4B is a potential effector of TGF-beta-induced cell cycle arrest.
    Nature. 1994 Sep 15;371(6494):257-61 PMID: 8078588
  50. TGF-beta induced transdifferentiation of mammary epithelial cells to mesenchymal cells: involvement of type I receptors.
    J Cell Biol. 1994 Dec;127(6 Pt 2):2021-36 PMID: 7806579
  51. Transforming growth factor beta activation of p44mapk in proliferating cultures of epithelial cells.
    J Biol Chem. 1995 Mar 31;270(13):7117-24 PMID: 7706248
  52. GS domain mutations that constitutively activate T beta R-I, the downstream signaling component in the TGF-beta receptor complex.
    EMBO J. 1995 May 15;14(10):2199-208 PMID: 7774578
  53. Kip/Cip and Ink4 Cdk inhibitors cooperate to induce cell cycle arrest in response to TGF-beta.
    Genes Dev. 1995 Aug 1;9(15):1831-45 PMID: 7649471
  54. Transforming growth factor-beta (TGF-beta)-induced down-regulation of cyclin A expression requires a functional TGF-beta receptor complex. Characterization of chimeric and truncated type I and type II receptors.
    J Biol Chem. 1995 Oct 13;270(41):24237-45 PMID: 7592630
  55. Transforming growth factor beta activates the promoter of cyclin-dependent kinase inhibitor p15INK4B through an Sp1 consensus site.
    J Biol Chem. 1995 Nov 10;270(45):26750-3 PMID: 7592908
  56. Functional analysis of the transforming growth factor beta responsive elements in the WAF1/Cip1/p21 promoter.
    J Biol Chem. 1995 Dec 1;270(48):28623-8 PMID: 7499379
  57. Receptor-associated Mad homologues synergize as effectors of the TGF-beta response.
    Nature. 1996 Sep 12;383(6596):168-72 PMID: 8774881
  58. Signaling inputs converge on nuclear effectors in TGF-beta signaling.
    Trends Biochem Sci. 2000 Feb;25(2):64-70 PMID: 10664585
Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
DOI
10.1093/emboj/cdf366
Published
2002-07-15
Pages
3749-59
Language
English
Region
England
NLM ID
8208664
PMCID
PMC126112
Subset
IM
Grants
Intramural NIH HHS · Z01 BC010419-08 · United States
External Links
PubMed source DOI: 10.1093/emboj/cdf366 PMC Full Text View journal details
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