uu.seUppsala University Publications
Change search
Link to record
Permanent link

Direct link
BETA
Yakymovych, Ihor
Publications (10 of 10) Show all publications
Yakymovych, I., Yakymovych, M. & Heldin, C.-H. (2018). Intracellular trafficking of transforming growth factor beta receptors. Acta biochimica et biophysica Sinica, 50(1), 3-11
Open this publication in new window or tab >>Intracellular trafficking of transforming growth factor beta receptors
2018 (English)In: Acta biochimica et biophysica Sinica, ISSN 1672-9145, Vol. 50, no 1, p. 3-11Article, review/survey (Refereed) Published
Abstract [en]

Transforming growth factor beta (TGF beta) family members signal via heterotetrameric complexes of type I (T beta RI) and type II (T beta RII) dual specificity kinase receptors. The availability of the receptors on the cell surface is controlled by several mechanisms. Newly synthesized T beta RI and T beta RII are delivered from the Golgi apparatus to the cell surface via separate routes. On the cell surface, TGF beta receptors are distributed between different microdomains of the plasma membrane and can be internalized via clathrin- and caveolae-mediated endocytic mechanisms. Although receptor endocytosis is not essential for TGF beta signaling, localization of the activated receptor complexes on the early endosomes promotes TGF beta-induced Smad activation. Caveolae-mediated endocytosis, which is widely regarded as a mechanism that facilitates the degradation of TGF beta receptors, has been shown to be required for TGF beta signaling via non-Smad pathways. The importance of proper control of TGF beta receptor intracellular trafficking is emphasized by clinical data, as mislocalization of receptors has been described in connection with several human diseases. Thus, control of intracellular trafficking of the TGF beta receptors together with the regulation of their expression, posttranslational modifications and down-regulation, ensure proper regulation of TGF beta signaling.

Place, publisher, year, edition, pages
Oxford University Press, 2018
Keyword
TGF beta receptor, endocytosis, clathrin, lipid rafts, endosome
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-350115 (URN)10.1093/abbs/gmx119 (DOI)000423304200002 ()29186283 (PubMedID)
Available from: 2018-05-07 Created: 2018-05-07 Last updated: 2018-05-07Bibliographically approved
Yakymovych, I., Yakymovych, M., Zang, G., Mu, Y., Bergh, A., Landström, M. & Heldin, C.-H. (2015). CIN85 modulates TGF beta signaling by promoting the presentation of TGF beta receptors on the cell surface. Journal of Cell Biology, 210(2), 319-332
Open this publication in new window or tab >>CIN85 modulates TGF beta signaling by promoting the presentation of TGF beta receptors on the cell surface
Show others...
2015 (English)In: Journal of Cell Biology, ISSN 0021-9525, E-ISSN 1540-8140, Vol. 210, no 2, p. 319-332Article in journal (Refereed) Published
Abstract [en]

Members of the transforming growth factor beta (TGF beta) family initiate cellular responses by binding to TGF beta receptor type II (Tf3R11) and type I (TpRI) serine/threonine kinases, whereby Srnad2 and Smad3 are phosphorylated and activated, promoting their association with Smadzi. We report here that T beta RI interacts with the SH3 domains of the adaptor protein CIN85 in response to TGF beta stimulation in a TRAF6-dependent manner. Small interfering RNA mediated knockdown of CIN85 resulted in accumulation of T beta RI in intracellular compartments and diminished TGF beta-stimulated Sniad2 phosphorylation. Overexpression of CIN85 instead increased the amount of T beta RI at the cell surface. This effect was inhibited by a dominant-negative mutant of Rab11, suggesting that CIN85 promoted recycling of TGF beta receptors. CIN85 enhanced TGF beta-stimulated Smad2 phosphorylation, transcriptional responses, and cell migration. CIN85 expression correlated with the degree of malignancy of prostate cancers. Collectively, our results reveal that CIN85 promotes recycling of TGF beta receptors and thereby positively regulates TGF beta signaling.

National Category
Cancer and Oncology Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-260622 (URN)10.1083/jcb.201411025 (DOI)000358457300012 ()
Funder
Knut and Alice Wallenberg Foundation, 2012.0090Swedish Cancer Society, 13 0688
Note

Funding: Ludwig Institute for Cancer Research, Swedish Medical Research Council  K2013-66X-15284-04-4

Available from: 2015-08-24 Created: 2015-08-21 Last updated: 2017-12-04Bibliographically approved
Iwahana, H., Yakymovych, I., Dubrovska, A., Hellman, U. & Souchelnytskyi, S. (2006). Glycoproteome profiling of transforming growth factor-beta (TGF beta) signaling: Nonglycosylated cell death-inducing DFF-like effector A inhibits TGF beta 1-dependent apoptosis. Proteomics, 6(23), 6168-6180
Open this publication in new window or tab >>Glycoproteome profiling of transforming growth factor-beta (TGF beta) signaling: Nonglycosylated cell death-inducing DFF-like effector A inhibits TGF beta 1-dependent apoptosis
Show others...
2006 (English)In: Proteomics, ISSN 1615-9853, E-ISSN 1615-9861, Vol. 6, no 23, p. 6168-6180Article in journal (Refereed) Published
Abstract [en]

Transforming growth factor-beta (TGFbeta) is a potent regulator of cell growth, differentiation, and apoptosis. TGFbeta binds to specific serine/threonine kinase receptors, which leads to activation of Smad-dependent and Smad-independent signaling pathways. O-Glycosylation is a dynamic PTM which has been observed in many regulatory proteins, but has not been studied in the context of TGFbeta signaling. To explore the effect of TGFbeta1 on protein O-glycosylation in human breast epithelial cells, we performed analyses of proteins which were affinity purified with Helix pomatia agglutinin (HPA). HPA lectin allowed enrichment of proteins containing GalNAc and GlcNAc linked to serine and threonine residues. Using 2-DE and MALDI-TOF-MS, we identified 21 HPA-precipitated proteins, which were affected by treatment of cells with TGFbeta1. Among these proteins, regulators of cell survival, apoptosis, trafficking, and RNA processing were identified. We found that TGFbeta1 inhibited the appearance of cell death-inducing DFF-like effector A (CIDE-A) in 2-D gels with HPA-precipitated proteins. CIDE-A is a cell death activator which promotes DNA fragmentation. We observed that TGFbeta1 did not affect expression of CIDE-A, but inhibited its glycosylation. We found that deglycosylation of CIDE-A correlated with enhanced nuclear export of the protein, and that high level of nonglycosylated CIDE-A inhibited TGFbeta1-dependent cell death. Thus, inhibition of the glycosylation of CIDE-A may be a mechanism to protect cells from apoptosis.

Keyword
Apoptosis, CIDE-A, Glycosylation, Transforming growth factor-β
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-19731 (URN)10.1002/pmic.200600384 (DOI)000242879000006 ()17080483 (PubMedID)
Available from: 2006-12-01 Created: 2006-12-01 Last updated: 2017-12-08Bibliographically approved
Stasyk, T., Dubrovska, A., Lomnytska, M., Yakymovych, I., Wernstedt, C., Heldin, C.-H., . . . Souchelnytskyi, S. (2005). Phosphoproteome profiling of transforming growth factor (TGF)-beta signaling: abrogation of TGFbeta1-dependent phosphorylation of transcription factor-II-I (TFII-I) enhances cooperation of TFII-I and Smad3 in transcription. Molecular Biology of the Cell, 16(10), 4765-4780
Open this publication in new window or tab >>Phosphoproteome profiling of transforming growth factor (TGF)-beta signaling: abrogation of TGFbeta1-dependent phosphorylation of transcription factor-II-I (TFII-I) enhances cooperation of TFII-I and Smad3 in transcription
Show others...
2005 (English)In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 16, no 10, p. 4765-4780Article in journal (Refereed) Published
Abstract [en]

Transforming growth factor-beta (TGFbeta) signaling involves activation of a number of signaling pathways, several of which are controlled by phosphorylation events. Here, we describe a phosphoproteome profiling of MCF-7 human breast epithelial cells treated with TGFbeta1. We identified 32 proteins that change their phosphorylation upon treatment with TGFbeta1; 26 of these proteins are novel targets of TGFbeta1. We show that Smad2 and Smad3 have different effects on the dynamics of TGFbeta1-induced protein phosphorylation. The identified proteins belong to nine functional groups, e.g., proteins regulating RNA processing, cytoskeletal rearrangements, and proteasomal degradation. To evaluate the proteomics findings, we explored the functional importance of TGFbeta1-dependent phosphorylation of one of the targets, i.e., transcription factor-II-I (TFII-I). We confirmed that TGFbeta1 stimulated TFII-I phosphorylation at serine residues 371 and 743. Abrogation of the phosphorylation by replacement of Ser371 and Ser743 with alanine residues resulted in enhanced complex formation between TFII-I and Smad3, and enhanced cooperation between TFII-I and Smad3 in transcriptional regulation, as evaluated by a microarray-based measurement of expression of endogenous cyclin D2, cyclin D3, and E2F2 genes, and by a luciferase reporter assay. Thus, TGFbeta1-dependent phosphorylation of TFII-I may modulate TGFbeta signaling at the transcriptional level.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-74760 (URN)10.1091/mbc.E05-03-0257 (DOI)16055503 (PubMedID)
Available from: 2005-11-14 Created: 2005-11-14 Last updated: 2017-12-14Bibliographically approved
Yakymovych, I., Heldin, C.-H. & Souchelnytskyi, S. (2004). Smad2 phosphorylation by type I receptor: contribution of arginine 462 and cysteine 463 In the C terminus of Smad2 for specificity. Journal of Biological Chemistry, 279(34), 35781-35787
Open this publication in new window or tab >>Smad2 phosphorylation by type I receptor: contribution of arginine 462 and cysteine 463 In the C terminus of Smad2 for specificity
2004 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 279, no 34, p. 35781-35787Article in journal (Refereed) Published
Abstract [en]

Transforming growth factor-beta (TGFbeta) is a potent regulator of cell proliferation, differentiation, motility, and apoptosis. TGFbeta binds to and activates serine/threonine kinase receptors that phosphorylate Smad2 and Smad3 intracellular signal transducers at two C-terminal serine residues. Here we show that substitutions of Arg-462 and Cys-463 residues, which are in proximity of the C-terminal serine residues, inhibited TGFbeta type I receptor-dependent phosphorylation of the C-terminal Smad2 peptides and full-length GST-Smad2 proteins in vitro. In vivo, mutation of Arg-462 and Cys-463 inhibited TGFbeta1-stimulated phosphorylation of the C-terminal serine residues in Smad2. Moreover, Smad2 with mutated Arg-462 and Cys-463 was less efficient in activation of the Smad2-responsive activin-responsive element-containing luciferase reporter ARE-luc, as compared with the wild-type protein. Thus, Arg-462 and Cys-463, which are in proximity of the C-terminal serine residues, contribute to recognition and phosphorylation of the C terminus of Smad2 by type I TGFbeta receptor.

Keyword
Activin Receptors; Type I/*metabolism, Amino Acid Substitution, Animals, Arginine, Binding Sites, COS Cells, Cercopithecus aethiops, Cysteine, DNA-Binding Proteins/*metabolism, Mice, Mutation, NIH 3T3 Cells, Phosphorylation, Protein Binding, Receptors; Transforming Growth Factor beta/*metabolism, Research Support; Non-U.S. Gov't, Substrate Specificity, Trans-Activators/*metabolism
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-72828 (URN)10.1074/jbc.M404377200 (DOI)15210694 (PubMedID)
Available from: 2005-05-30 Created: 2005-05-30 Last updated: 2017-12-14Bibliographically approved
Sjöblom, T., Yakymovych, I., Heldin, C.-H., Östman, A. & Souchelnytskyi, S. (2004). Smad2 suppresses the growth of Mv1Lu cells subcutaneously inoculated in mice. European Journal of Cancer, 40(2), 267-274
Open this publication in new window or tab >>Smad2 suppresses the growth of Mv1Lu cells subcutaneously inoculated in mice
Show others...
2004 (English)In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 40, no 2, p. 267-274Article in journal (Refereed) Published
Abstract [en]

Smad2 and Smad3 are intracellular signal transduction proteins of importance in transforming growth factor-beta (TGFbeta)-mediated inhibition of epithelial cell proliferation. Inactivating mutations in the Smad2 and Smad3 genes have been found in various human malignancies. Here, we show that expression of Smad2 leads to the inhibition of growth of Mv1Lu cells inoculated with Matrigel subcutaneously (s.c.) in severe combined immunodeficient (SCID) mice. In histological appearance, the Matrigel plugs with Smad2-transfected cells showed strongly reduced cell density, proliferation and angiogenesis compared with the small tumour nodules of similar size formed by the vector- or Smad3-transfected cells. The histological appearance of vector- and Smad3-transfected cells inoculated in mice was identical. Overexpression of Smad2 and Smad3 in Mv1Lu cells led to the inhibition of cell growth in three-dimensional cultures when compared with vector-transfected cells. Overexpression of Smad2 and Smad3 also decreased the hyperphosphorylation of pRb in Smad-transfected cells. Thus, increased expression of Smad2 leads to inhibition of Mv1Lu cell proliferation and a reduction in the growth of the Smad2-expressing cells inoculated in mice.

Keyword
Animals, Blotting; Western, DNA-Binding Proteins/*genetics, Gene Expression, Genes; myc/genetics, Immunohistochemistry, Keratinocytes, Lung Neoplasms/*pathology, Mice, Mice; SCID, Neoplasm Transplantation, Phosphorylation, Proteins/genetics, Research Support; Non-U.S. Gov't, Trans-Activators/*genetics, Transfection, Tumor Cells; Cultured
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-72958 (URN)10.1016/j.ejca.2003.08.016 (DOI)14728942 (PubMedID)
Available from: 2005-05-31 Created: 2005-05-31 Last updated: 2017-12-14Bibliographically approved
Stoika, R., Yakymovych, M., Souchelnytskyi, S. & Yakymovych, I. (2003). Potential role of transforming growth factor beta1 in drug resistance of tumor cells. Acta Biochimica Polonica, 50(2), 497-508
Open this publication in new window or tab >>Potential role of transforming growth factor beta1 in drug resistance of tumor cells
2003 (English)In: Acta Biochimica Polonica, ISSN 0001-527X, E-ISSN 1734-154X, Vol. 50, no 2, p. 497-508Article in journal (Refereed) Published
Abstract [en]

Acquired drug resistance of tumor cells is frequently observed in cancer patients undergoing chemotherapy. We studied murine leukemia L1210 cells sensitive and resistant to the cytotoxic action of cisplatin and showed that cisplatin-resistant leukemia cells were also refractory to TGF beta1-dependent growth inhibition and apoptosis. Addressing the question about the mechanisms responsible for the cross-resistance to cisplatin and TGF beta1, we found that cisplatin- and TGF beta1-resistant L1210 cells possessed a decreased expression of type I TGF beta1 receptor, while the expression of type II TGF beta1 receptor was not affected. Western blot analysis of Smad proteins 2, 3, 4, 6, and 7, which participate in signal transduction pathway down-stream of the TGF beta1 receptors, revealed an increased expression of Smad 6, inhibiting TGF beta1 action, only in cisplatin- and TGF beta1-resistant L1210 cells. TGF beta1 and especially the cytotoxic mistletoe agglutinin increased Smad 6 expression in TGF beta1-sensitive but not in TGF beta1-resistant L1210 cells. TGF beta1-resistant L1210 cells also differed from TGF beta1-sensitive cells by the lack of expression of the pro-apoptotic p53 protein and higher level of expression of the anti-apoptotic Bcl-2 protein. Thus, the described co-expression of tumor cell refractoriness to an anti-cancer drug and to the inhibitory cytokine TGF beta1 is accompanied by multiple changes in the TGF beta1 signal transduction pathway and in other regulatory systems of the target cells. Besides, we found that various anti-tumor drugs and cytotoxic plant lectins increased the level of TGF beta1 expression in both TGFbeta1-sensitive and -resistant L1210 cells. A hypothesis is proposed that TGFbeta1 can at least partly mediate the effect of cell-stressing agents and, thus, the development of TGF beta1 resistance may be responsible for the appearance of tumor cell refractoriness to the action of some anti-cancer drugs.

Keyword
Animals, Antineoplastic Agents/*pharmacology, Apoptosis/drug effects, Cell Count, Cell Division/drug effects, Cell Line; Tumor, Cisplatin/*pharmacology, DNA Fragmentation/drug effects, DNA-Binding Proteins/biosynthesis, Drug Resistance; Multiple, Drug Resistance; Neoplasm, Lectins/pharmacology, Leukemia L1210/drug therapy/metabolism/pathology, Mice, Proto-Oncogene Proteins c-bcl-2/biosynthesis, Receptors; Transforming Growth Factor beta/biosynthesis, Signal Transduction, Smad Proteins, Time Factors, Trans-Activators/biosynthesis, Transforming Growth Factor beta/metabolism/*pharmacology, Transforming Growth Factor beta1, Tumor Suppressor Protein p53/biosynthesis
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-10424 (URN)12833174 (PubMedID)
Available from: 2007-03-22 Created: 2007-03-22 Last updated: 2017-12-11Bibliographically approved
Preobrazhenska, O., Yakymovych, M., Kanamoto, T., Yakymovych, I., Stoika, R., Heldin, C.-H. & Souchelnytskyi, S. (2002). BRCA2 and Smad3 synergize in regulation of gene transcription. Oncogene, 21(36), 5660-5664
Open this publication in new window or tab >>BRCA2 and Smad3 synergize in regulation of gene transcription
Show others...
2002 (English)In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 21, no 36, p. 5660-5664Article in journal (Refereed) Published
Abstract [en]

Smad3 is an essential component in the intracellular signaling of transforming growth factor-beta (TGFbeta), which is a potent inhibitor of tumor cell proliferation. BRCA2 is a tumor suppressor involved in early onset of breast, ovarian and prostate cancer. Both Smad3 and BRCA2 possess transcription activation domains. Here, we show that Smad3 and BRCA2 interact functionally and physically. We found that BRCA2 forms a complex with Smad3 in vitro and in vivo, and that both MH1 and MH2 domains of Smad3 contribute to the interaction. TGFbeta1 stimulates interaction of endogenous Smad3 and BRCA2 in non-transfected cells. BRCA2 co-activates Smad3-dependent transcriptional activation of luciferase reporter and expression of plasminogen activator inhibitor-1 (PAI-1). Smad3 increases the transcriptional activity of BRCA2 fused to the DNA-binding domain (DBD) of Gal4, and reciprocally, BRCA2 co-activates DBD-Gal4-Smad3. Thus, our results show that BRCA2 and Smad3 form a complex and synergize in regulation of transcription.

Keyword
BRCA2 Protein/*genetics, Binding Sites, Blotting; Western, Breast Neoplasms/*genetics/metabolism, DNA-Binding Proteins/*genetics/metabolism, Drug Synergism, Female, Gene Expression Regulation; Neoplastic, Genes; Reporter/genetics, Glutathione Transferase/metabolism, Humans, Plasmids, Protein Binding, Signal Transduction, Smad3 Protein, Trans-Activation (Genetics), Trans-Activators/*genetics/metabolism, Transcription; Genetic, Transforming Growth Factor beta/metabolism/*pharmacology, Tumor Cells; Cultured
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-10421 (URN)12165866 (PubMedID)
Available from: 2007-03-22 Created: 2007-03-22 Last updated: 2017-12-11Bibliographically approved
Yakymovych, I., Engström, U., Grimsby, S., Heldin, C.-H. & Souchelnytskyi, S. (2002). Inhibition of transforming growth factor-beta signaling by low molecular weight compounds interfering with ATP- or substrate-binding sites of the TGF beta type I receptor kinase. Biochemistry, 41(36), 11000-11007
Open this publication in new window or tab >>Inhibition of transforming growth factor-beta signaling by low molecular weight compounds interfering with ATP- or substrate-binding sites of the TGF beta type I receptor kinase
Show others...
2002 (English)In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 41, no 36, p. 11000-11007Article in journal (Refereed) Published
Abstract [en]

Transforming growth factor-beta (TGFbeta) is a potent regulator of cell proliferation, differentiation, apoptosis, and migration. TGF-beta type I receptor (TbetaR-I), which has intrinsic serine/threonine kinase activity, is a key component in activation of intracellular TGFbeta signaling. We studied two different classes of TbetaR-I inhibitors, i.e., compounds interfering with the ATP-binding site of the kinase and substrate-mimicking peptides. We found that pyridinylimidazole compounds inhibited TbetaR-I kinase at micromolar concentration. A representative compound, SB203580, inhibited in vivo Smad2 phosphorylation by TbetaR-I and affected TGFbeta-dependent transcriptional activation. Peptides mimicking the TbetaR-I phosphorylation sites at the C-terminus of Smad2 also inhibited the autophosphorylation of TbetaR-I and phosphorylation of Smad2 by TbetaR-I in vitro and in vivo, whereas a similar peptide from Smad5 was without effect. The substrate-mimicking peptide, fused to penetratin, inhibited a TGFbeta1-dependent transcriptional response in a luciferase reporter assay and ligand-dependent growth inhibition of Mv1Lu cells. Thus, the substrate-mimetic peptide is a new type of specific inhibitor of the TGFbeta signaling in vivo.

Keyword
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/pharmacology, Adenosine Triphosphate/antagonists & inhibitors/*metabolism, Amino Acid Sequence, Animals, Antennapedia Homeodomain Protein, Binding Sites/drug effects, COS Cells, Cell Line, DNA-Binding Proteins/metabolism/pharmacology, Enzyme Inhibitors/pharmacology, Homeodomain Proteins/pharmacology, Imidazoles/pharmacology, Mink, Molecular Mimicry, Molecular Sequence Data, Molecular Weight, Nuclear Proteins, Peptide Fragments/chemical synthesis/pharmacology, Protein-Serine-Threonine Kinases/*antagonists & inhibitors/genetics/metabolism, Pyridines/pharmacology, Receptors; Transforming Growth Factor beta/*antagonists & inhibitors/metabolism, Recombinant Fusion Proteins/chemical synthesis/pharmacology, Signal Transduction/drug effects, Smad2 Protein, Smad3 Protein, Substrate Specificity, Trans-Activators/metabolism/pharmacology, Transcription Factors, Transforming Growth Factor beta/*antagonists & inhibitors/metabolism/*physiology
National Category
Natural Sciences
Identifiers
urn:nbn:se:uu:diva-10420 (URN)10.1021/bi025936u (DOI)12206672 (PubMedID)
Available from: 2007-03-22 Created: 2007-03-22 Last updated: 2017-12-11Bibliographically approved
Yakymovych, I., ten Dijke, P., Heldin, C.-H. & Souchelnytskyi, S. (2001). Regulation of Smad signaling by protein kinase C. The FASEB Journal, 15(3), 553-555
Open this publication in new window or tab >>Regulation of Smad signaling by protein kinase C
2001 (English)In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 15, no 3, p. 553-555Article in journal (Refereed) Published
Abstract [en]

Cross talk between transforming growth factor beta(TGF-beta) serine/threonine kinase receptor signaling and tyrosine kinase receptor signaling modulates cell responsiveness to polypeptide growth factors regulating cell proliferation, differentiation, and apoptosis. Here we provide a mechanism through which Smad-dependent TGF-beta signaling is modulated by protein kinase C (PKC). PKC, for example, is activated downstream of tyrosine kinase receptors. We show that PKC directly phosphorylates receptor-regulated Smad proteins. This phosphorylation abrogates the ability of Smad3 to bind directly to DNA, which leads to subsequent inability to mediate transcriptional responses dependent on the direct binding of Smad3 to DNA. Interference with PKC regulation of Smad functions increased cell sensitivity to transformation by the tumor promoter phorbol 12-myristate 13-acetate (PMA). PKC-dependent phosphorylation of Smad3 was found also to be a key event in the PMA-dependent inactivation of TGF-beta-stimulated cell death. Thus, PKC-dependent phosphorylation of Smad3 leads to down-regulation of the growth inhibitory and apoptotic action of TGF-beta.

Keyword
1-Phosphatidylinositol 3-Kinase/metabolism, Cell Line, DNA/metabolism, DNA-Binding Proteins/genetics/*metabolism, Isoenzymes/metabolism, Mitogen-Activated Protein Kinases/metabolism, Models; Molecular, Peptide Fragments/*metabolism, Phospholipase C/metabolism, Phosphorylation, Protein Kinase C/*metabolism, Recombinant Fusion Proteins/metabolism, Signal Transduction, Tetradecanoylphorbol Acetate/*pharmacology, Trans-Activators/genetics/*metabolism, Transfection, Transforming Growth Factor beta/*metabolism
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-73361 (URN)10.1096/fj.00-0474fje (DOI)11259364 (PubMedID)
Available from: 2005-06-02 Created: 2005-06-02 Last updated: 2017-12-14Bibliographically approved
Organisations

Search in DiVA

Show all publications