Home LiteratureArticle Details
PMID: 18469808 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

The type I TGF-beta receptor is covalently modified and regulated by sumoylation.

Nature cell biology ·Vol. 10 ·No. 6 ·2008-06-00 ·Pages 654-64

Kang JS, Saunier EF, Akhurst RJ, Derynck R

Abstract

Post-translational sumoylation, the covalent attachment of a small ubiquitin-like modifier (SUMO), regulates the functions of proteins engaged in diverse processes. Often associated with nuclear and perinuclear proteins, such as transcription factors, it is not known whether SUMO can conjugate to cell-surface receptors for growth factors to regulate their functions. Here we show that the type I transforming growth factor-beta (TGF-beta) receptor, T beta RI, is sumoylated in response to TGF-beta and that its sumoylation requires the kinase activities of both T beta RI and the type II TGF-beta receptor, T beta RII. Sumoylation of T beta RI enhances receptor function by facilitating the recruitment and phosphorylation of Smad3, consequently regulating TGF-beta-induced transcription and growth inhibition. T beta RI sumoylation modulates the dissemination of transformed cells in a mouse model of T beta RI-stimulated metastasis. T beta RI sumoylation therefore controls responsiveness to TGF-beta, with implications for tumour progression. Sumoylation of cell-surface receptors may regulate other growth factor responses.

MeSH Terms
Animals COS Cells Chlorocebus aethiops Cytoplasm/metabolism Gene Expression Regulation Humans Lysine/chemistry Mice Models, Biological Neoplasm Metastasis Phosphorylation Protein Binding Protein Serine-Threonine Kinases/metabolism,physiology Receptor, Transforming Growth Factor-beta Type I Receptors, Transforming Growth Factor beta/metabolism,physiology SUMO-1 Protein/metabolism Transforming Growth Factor beta/metabolism
Chemicals
Receptors, Transforming Growth Factor beta SUMO-1 Protein Transforming Growth Factor beta Protein Serine-Threonine Kinases Receptor, Transforming Growth Factor-beta Type I Lysine
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Kang Jong Seok
Department of Cell and Tissue Biology, Program in Cell Biology, University of California - San Francisco, California 94143, USA.
Saunier Elise F
Akhurst Rosemary J
Derynck Rik
References (43)
43 references, click to expand
  1. SUMO-1 modification of Mdm2 prevents its self-ubiquitination and increases Mdm2 ability to ubiquitinate p53.
    Cell. 2000 Jun 23;101(7):753-62 PMID: 10892746
  2. Sumoylation silences the plasma membrane leak K+ channel K2P1.
    Cell. 2005 Apr 8;121(1):37-47 PMID: 15820677
  3. Roles of autocrine TGF-beta receptor and Smad signaling in adipocyte differentiation.
    J Cell Biol. 2000 May 1;149(3):667-82 PMID: 10791980
  4. Direct binding of Smad3 and Smad4 to critical TGF beta-inducible elements in the promoter of human plasminogen activator inhibitor-type 1 gene.
    EMBO J. 1998 Jun 1;17(11):3091-100 PMID: 9606191
  5. Sumoylation of Smad4, the common Smad mediator of transforming growth factor-beta family signaling.
    J Biol Chem. 2003 Jul 25;278(30):27853-63 PMID: 12740389
  6. Ubiquitin-dependent regulation of TGFbeta signaling in cancer.
    Neoplasia. 2006 Aug;8(8):677-88 PMID: 16925950
  7. TGFbeta signaling is necessary for carcinoma cell invasiveness and metastasis.
    Curr Biol. 1998 Nov 19;8(23):1243-52 PMID: 9822576
  8. Human transforming growth factor-beta 3: recombinant expression, purification, and biological activities in comparison with transforming growth factors-beta 1 and -beta 2.
    Mol Endocrinol. 1989 Dec;3(12):1977-86 PMID: 2628733
  9. Smurf1 interacts with transforming growth factor-beta type I receptor through Smad7 and induces receptor degradation.
    J Biol Chem. 2001 Apr 20;276(16):12477-80 PMID: 11278251
  10. Ligand-independent activation of transforming growth factor (TGF) beta signaling pathways by heteromeric cytoplasmic domains of TGF-beta receptors.
    J Biol Chem. 1996 May 31;271(22):13123-9 PMID: 8662796
  11. Negative regulation of transforming growth factor-beta (TGF-beta) signaling by WW domain-containing protein 1 (WWP1).
    Oncogene. 2004 Sep 9;23(41):6914-23 PMID: 15221015
  12. NEDD4-2 (neural precursor cell expressed, developmentally down-regulated 4-2) negatively regulates TGF-beta (transforming growth factor-beta) signalling by inducing ubiquitin-mediated degradation of Smad2 and TGF-beta type I receptor.
    Biochem J. 2005 Mar 15;386(Pt 3):461-70 PMID: 15496141
  13. The role of chromatin during transcription.
    Cell. 2007 Feb 23;128(4):707-19 PMID: 17320508
  14. Patterns of somatic mutation in human cancer genomes.
    Nature. 2007 Mar 8;446(7132):153-8 PMID: 17344846
  15. Metastasis is driven by sequential elevation of H-ras and Smad2 levels.
    Nat Cell Biol. 2002 Jul;4(7):487-94 PMID: 12105419
  16. Roles of sumoylation of a reptin chromatin-remodelling complex in cancer metastasis.
    Nat Cell Biol. 2006 Jun;8(6):631-9 PMID: 16699503
  17. Specificity and versatility in tgf-beta signaling through Smads.
    Annu Rev Cell Dev Biol. 2005;21:659-93 PMID: 16212511
  18. Smad transcription factors.
    Genes Dev. 2005 Dec 1;19(23):2783-810 PMID: 16322555
  19. Protein modification by SUMO.
    Annu Rev Biochem. 2004;73:355-82 PMID: 15189146
  20. 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
  21. Activin receptor-like kinases: a novel subclass of cell-surface receptors with predicted serine/threonine kinase activity.
    Oncogene. 1993 Oct;8(10):2879-87 PMID: 8397373
  22. Covalent attachment of the SUMO-1 protein to the negative regulatory domain of the c-Myb transcription factor modifies its stability and transactivation capacity.
    J Biol Chem. 2002 Mar 15;277(11):8999-9009 PMID: 11779867
  23. The tumor suppressor Smad4/DPC4 and transcriptional adaptor CBP/p300 are coactivators for smad3 in TGF-beta-induced transcriptional activation.
    Genes Dev. 1998 Jul 15;12(14):2153-63 PMID: 9679060
  24. SUMO-1 modification activates the transcriptional response of p53.
    EMBO J. 1999 Nov 15;18(22):6455-61 PMID: 10562557
  25. SUMOylation regulates kainate-receptor-mediated synaptic transmission.
    Nature. 2007 May 17;447(7142):321-5 PMID: 17486098
  26. Alterations in components of the TGF-beta superfamily signaling pathways in human cancer.
    Cytokine Growth Factor Rev. 2006 Feb-Apr;17(1-2):41-58 PMID: 16310402
  27. Abnormal angiogenesis but intact hematopoietic potential in TGF-beta type I receptor-deficient mice.
    EMBO J. 2001 Apr 2;20(7):1663-73 PMID: 11285230
  28. A single missense mutant of Smad3 inhibits activation of both Smad2 and Smad3, and has a dominant negative effect on TGF-beta signals.
    FEBS Lett. 1998 Jul 3;430(3):201-4 PMID: 9688538
  29. TGF-beta signaling in tumor suppression and cancer progression.
    Nat Genet. 2001 Oct;29(2):117-29 PMID: 11586292
  30. SUMO modification regulates inactivation of the voltage-gated potassium channel Kv1.5.
    Proc Natl Acad Sci U S A. 2007 Feb 6;104(6):1805-10 PMID: 17261810
  31. Transforming growth factor beta type I receptor kinase mutant associated with metastatic breast cancer.
    Cancer Res. 1998 Nov 1;58(21):4805-10 PMID: 9809982
  32. Post-translational modification of p53 in tumorigenesis.
    Nat Rev Cancer. 2004 Oct;4(10):793-805 PMID: 15510160
  33. Characterization of type I receptors for transforming growth factor-beta and activin.
    Science. 1994 Apr 1;264(5155):101-4 PMID: 8140412
  34. 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
  35. Improved retroviral vectors for gene transfer and expression.
    Biotechniques. 1989 Oct;7(9):980-2, 984-6, 989-90 PMID: 2631796
  36. PDSM, a motif for phosphorylation-dependent SUMO modification.
    Proc Natl Acad Sci U S A. 2006 Jan 3;103(1):45-50 PMID: 16371476
  37. Repression of Runx2 function by TGF-beta through recruitment of class II histone deacetylases by Smad3.
    EMBO J. 2005 Jul 20;24(14):2543-55 PMID: 15990875
  38. Smad7 binds to Smurf2 to form an E3 ubiquitin ligase that targets the TGF beta receptor for degradation.
    Mol Cell. 2000 Dec;6(6):1365-75 PMID: 11163210
  39. Cellular transformation and malignancy induced by ras require c-jun.
    Mol Cell Biol. 1996 Aug;16(8):4504-11 PMID: 8754851
  40. Mechanisms of transforming growth factor-beta receptor endocytosis and intracellular sorting differ between fibroblasts and epithelial cells.
    Mol Biol Cell. 2001 Mar;12(3):675-84 PMID: 11251079
  41. Members of the PIAS family act as SUMO ligases for c-Jun and p53 and repress p53 activity.
    Proc Natl Acad Sci U S A. 2002 Mar 5;99(5):2872-7 PMID: 11867732
  42. Control of Smad7 stability by competition between acetylation and ubiquitination.
    Mol Cell. 2002 Sep;10(3):483-93 PMID: 12408818
  43. Novel inactivating mutations of transforming growth factor-beta type I receptor gene in head-and-neck cancer metastases.
    Int J Cancer. 2001 Sep 1;93(5):653-61 PMID: 11477574
Article Info
Journal
Nature cell biology
Abbr.
Nat Cell Biol
ISSN
1476-4679
DOI
10.1038/ncb1728
Published
2008-06-00
Epub
2008-00-11
Pages
654-64
Language
English
Region
England
NLM ID
100890575
PMCID
PMC2649123
Subset
IM
Grants
NHLBI NIH HHS · R01 HL078564 · United States
NCI NIH HHS · R01 CA063101 · United States
NIAMS NIH HHS · P01 AR050440 · United States
NCI NIH HHS · R21 CA125190 · United States
NCI NIH HHS · R21 CA125190-01 · United States
NCI NIH HHS · R01 CA116019 · United States
NCI NIH HHS · R01 CA116019-03 · United States
NCI NIH HHS · R21-CA125190 · United States
NCI NIH HHS · R21 CA125190-02 · United States
NCI NIH HHS · R01-CA63101 · United States
External Links
PubMed source DOI: 10.1038/ncb1728 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2