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PMID: 2022183 Published · ppublish English Journal Article

A role of the latent TGF-beta 1-binding protein in the assembly and secretion of TGF-beta 1.

The EMBO journal ·Vol. 10 ·No. 5 ·1991-05-00 ·Pages 1091-101

Miyazono K, Olofsson A, Colosetti P, Heldin CH

Abstract

Transforming growth factor-beta 1 (TGF-beta 1) is synthesized as latent complexes with high molecular weights. The large latent complex of TGF-beta 1 in platelets is composed of three components, i.e. the mature TGF-beta 1, which is non-covalently associated with a disulphide-bonded complex of the N-terminal remnant of the TGF-beta 1 precursor (TGF-beta 1-latency associated peptide) and the latent TGF-beta 1 binding protein (LTBP). The TGF-beta 1-latency associated peptide is sufficient for the latency of TGF-beta 1, whereas the functions of LTBP remain to be elucidated. In a human erythroleukemia cell line, HEL, the production of the latent form of TGF-beta 1 was induced more than 100-fold by phorbol 12-myristate 13-acetate. Analysis by Northern blotting revealed that both the TGF-beta 1 precursor and LTBP were induced in a coordinated fashion. Analysis by immunoprecipitation using antibodies against LTBP and the TGF-beta 1 precursor dimer revealed that LTBP has a molecular size of 205 kd under reducing conditions in this cell type, i.e. similar to that from cells transfected with cDNA for LTBP, but larger than the platelet form (125-160 kd). Limited tryptic digestion of LTBP in HEL cells and analysis by SDS-PAGE showed protein bands of similar sizes to those of platelet LTBP, suggesting that the difference in molecular sizes of LTBP involves cell-specific processing. The biosynthesis of the latent TGF-beta 1 was studied by pulse-chase analysis. LTBP became covalently associated with the TGF-beta 1 precursor within 15 min after synthesis in this cell line. Secretion of the large latent TGF-beta 1 complex was observed as early as 30 min after the synthesis of LTBP; at the same time, a free form of LTBP not bound to the TGF-beta 1 precursor was seen. In contrast, the TGF-beta 1 precursor remained inside the cells in an unprocessed form for a longer time period and the TGF-beta 1 precursor dimer without LTBP was secreted only very slowly. Furthermore, the results of partial tryptic digestion of this molecule suggested that it contained improper disulphide bonding. These results suggest that LTBP plays a critical role in the assembly and secretion of the latent TGF-beta 1.

MeSH Terms
Carrier Proteins/biosynthesis Humans Hydrolysis Intracellular Signaling Peptides and Proteins Latent TGF-beta Binding Proteins Leukemia, Erythroblastic, Acute/metabolism Molecular Weight Precipitin Tests Protein Precursors/metabolism Tetradecanoylphorbol Acetate/pharmacology Transforming Growth Factor beta/biosynthesis,metabolism Trypsin/pharmacology Tumor Cells, Cultured/drug effects
Chemicals
Carrier Proteins Intracellular Signaling Peptides and Proteins Latent TGF-beta Binding Proteins Protein Precursors Transforming Growth Factor beta Trypsin Tetradecanoylphorbol Acetate
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Miyazono K
Ludwig Institute for Cancer Research, Biomedical Center, Uppsala, Sweden.
Olofsson A
Colosetti P
Heldin C H
References (41)
41 references, click to expand
  1. Purification and properties of an endothelial cell growth factor from human platelets.
    J Biol Chem. 1987 Mar 25;262(9):4098-103 PMID: 3549724
  2. Retinoic acid induces transforming growth factor-beta 2 in cultured keratinocytes and mouse epidermis.
    Cell Regul. 1989 Nov;1(1):87-97 PMID: 2519621
  3. Distribution and modulation of the cellular receptor for transforming growth factor-beta.
    J Cell Biol. 1987 Aug;105(2):965-75 PMID: 2887577
  4. Type 1 transforming growth factor beta: amplified expression and secretion of mature and precursor polypeptides in Chinese hamster ovary cells.
    Mol Cell Biol. 1987 Oct;7(10):3418-27 PMID: 3479680
  5. Enhanced expression of transforming growth factor beta during megakaryoblastic differentiation of K562 leukemia cells.
    Blood. 1988 Apr;71(4):899-906 PMID: 3162693
  6. Latent high molecular weight complex of transforming growth factor beta 1. Purification from human platelets and structural characterization.
    J Biol Chem. 1988 May 5;263(13):6407-15 PMID: 3162913
  7. An improved method of purification of transforming growth factor, type beta from platelets.
    Anal Biochem. 1988 Jan;168(1):71-4 PMID: 3163238
  8. Latent transforming growth factor-beta from human platelets. A high molecular weight complex containing precursor sequences.
    J Biol Chem. 1988 Jun 5;263(16):7646-54 PMID: 3163692
  9. Transfer of proteins across membranes. I. Presence of proteolytically processed and unprocessed nascent immunoglobulin light chains on membrane-bound ribosomes of murine myeloma.
    J Cell Biol. 1975 Dec;67(3):835-51 PMID: 811671
  10. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease.
    Biochemistry. 1979 Nov 27;18(24):5294-9 PMID: 518835
  11. Expression of platelet membrane glycoproteins and alpha-granule proteins by a human erythroleukemia cell line (HEL).
    EMBO J. 1984 Feb;3(2):453-9 PMID: 6201359
  12. Latent beta-transforming growth factor in nontransformed and Kirsten sarcoma virus-transformed normal rat kidney cells, clone 49F.
    Cancer Res. 1984 Dec;44(12 Pt 1):5538-43 PMID: 6093998
  13. Human transforming growth factor-beta complementary DNA sequence and expression in normal and transformed cells.
    Nature. 1985 Aug 22-28;316(6030):701-5 PMID: 3861940
  14. The transforming growth factor-beta system, a complex pattern of cross-reactive ligands and receptors.
    Cell. 1987 Feb 13;48(3):409-15 PMID: 2879635
  15. Constitutive and inducible secretion of platelet-derived growth factor analogs by human leukemic cell lines coexpressing erythroid and megakaryocytic markers.
    J Clin Invest. 1987 Mar;79(3):859-66 PMID: 3469217
  16. Molecular events in the processing of recombinant type 1 pre-pro-transforming growth factor beta to the mature polypeptide.
    Mol Cell Biol. 1988 Oct;8(10):4162-8 PMID: 3185545
  17. Identification and structural analysis of the A type receptor for platelet-derived growth factor. Similarities with the B type receptor.
    J Biol Chem. 1989 Jan 25;264(3):1742-7 PMID: 2536372
  18. High-yield purification of platelet-derived endothelial cell growth factor: structural characterization and establishment of a specific antiserum.
    Biochemistry. 1989 Feb 21;28(4):1704-10 PMID: 2541763
  19. Site-directed mutagenesis of cysteine residues in the pro region of the transforming growth factor beta 1 precursor. Expression and characterization of mutant proteins.
    J Biol Chem. 1989 Aug 15;264(23):13660-4 PMID: 2474534
  20. Transforming growth factor beta 1: importance of glycosylation and acidic proteases for processing and secretion.
    Mol Endocrinol. 1989 Jul;3(7):1090-8 PMID: 2677679
  21. Production of platelet-derived endothelial cell growth factor by normal and transformed human cells in culture.
    Proc Natl Acad Sci U S A. 1989 Oct;86(19):7427-31 PMID: 2678104
  22. Purification and structural analysis of a latent form of transforming growth factor-beta from rat platelets.
    J Biochem. 1989 Aug;106(2):304-10 PMID: 2478527
  23. Activation of the second promoter of the transforming growth factor-beta 1 gene by transforming growth factor-beta 1 and phorbol ester occurs through the same target sequences.
    J Biol Chem. 1989 Nov 15;264(32):19373-8 PMID: 2808430
  24. Complex regulation of transforming growth factor beta 1, beta 2, and beta 3 mRNA expression in mouse fibroblasts and keratinocytes by transforming growth factors beta 1 and beta 2.
    Mol Cell Biol. 1989 Dec;9(12):5508-15 PMID: 2586525
  25. Transforming growth factors and the regulation of cell proliferation.
    Eur J Biochem. 1990 Feb 14;187(3):467-73 PMID: 2406131
  26. Recombinant TGF-beta 1 is synthesized as a two-component latent complex that shares some structural features with the native platelet latent TGF-beta 1 complex.
    Growth Factors. 1989;1(3):203-18 PMID: 2629880
  27. The production of transforming growth factor-beta in acute megakaryoblastic leukemia and its possible implications in myelofibrosis.
    Blood. 1990 Apr 1;75(7):1540-8 PMID: 2317561
  28. TGF-beta 1 binding protein: a component of the large latent complex of TGF-beta 1 with multiple repeat sequences.
    Cell. 1990 Jun 15;61(6):1051-61 PMID: 2350783
  29. Transactivation of the transforming growth factor beta 1 (TGF-beta 1) gene by human T lymphotropic virus type 1 tax: a potential mechanism for the increased production of TGF-beta 1 in adult T cell leukemia.
    J Exp Med. 1990 Jul 1;172(1):121-9 PMID: 2358774
  30. Physicochemical activation of recombinant latent transforming growth factor-beta's 1, 2, and 3.
    Growth Factors. 1990;3(1):35-43 PMID: 2200452
  31. The pro domain of pre-pro-transforming growth factor beta 1 when independently expressed is a functional binding protein for the mature growth factor.
    Biochemistry. 1990 Jul 24;29(29):6851-7 PMID: 2397217
  32. TGF-beta stimulation and inhibition of cell proliferation: new mechanistic insights.
    Cell. 1990 Oct 19;63(2):245-7 PMID: 2208284
  33. Novel type of very high affinity calcium-binding sites in beta-hydroxyasparagine-containing epidermal growth factor-like domains in vitamin K-dependent protein S.
    J Biol Chem. 1990 Oct 25;265(30):18481-9 PMID: 2145284
  34. Sequence analysis of the promoter region of the glioblastoma derived T cell suppressor factor/transforming growth factor (TGF)-beta 2 gene reveals striking differences to the TGF-beta 1 and -beta 3 genes.
    Biochem Biophys Res Commun. 1990 Sep 28;171(3):1145-51 PMID: 2222434
  35. Structural and functional characterization of the transforming growth factor beta 3 promoter. A cAMP-responsive element regulates basal and induced transcription.
    J Biol Chem. 1990 Nov 5;265(31):19128-36 PMID: 2146270
  36. A phorbol ester-regulated ribonuclease system controlling transforming growth factor beta 1 gene expression in hematopoietic cells.
    Mol Cell Biol. 1990 Nov;10(11):5983-90 PMID: 2233728
  37. Molecular cloning of the large subunit of transforming growth factor type beta masking protein and expression of the mRNA in various rat tissues.
    Proc Natl Acad Sci U S A. 1990 Nov;87(22):8835-9 PMID: 2247454
  38. The transforming growth factor-beta family.
    Annu Rev Cell Biol. 1990;6:597-641 PMID: 2177343
  39. The many faces of epidermal growth factor repeats.
    New Biol. 1990 May;2(5):410-9 PMID: 2288911
  40. Latent forms of TGF-beta: molecular structure and mechanisms of activation.
    Ciba Found Symp. 1991;157:81-9; discussion 89-92 PMID: 2070685
  41. Intron-exon structure of the human transforming growth factor-beta precursor gene.
    Nucleic Acids Res. 1987 Apr 10;15(7):3188-9 PMID: 3470709
Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
Published
1991-05-00
Pages
1091-101
Language
English
Region
England
NLM ID
8208664
PMCID
PMC452762
Subset
IM
External Links
PubMed source PMC Full Text View journal details
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