Plasmin cleaves betaglycan and releases a 60 kDa transforming growth factor-<i>β</i> complex from the cell surface

LaMarre, Jonathan; Vasudevan, Jayanand; Gonias, Steven L.

doi:10.1042/bj3020199

Cited by 41 publications

(17 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Alternatively, proteoglycans could be secreted by stromal cells and function as co-receptors for growth factors, a mechanism that was described recently for the binding of tumor growth factor-␤ (TGF-␤) to its receptor. 41,42 Whether leukemic cells have different stroma requirements than normal progenitors is not known.…”

Section: Figurementioning

confidence: 99%

Stromal cells prevent apoptosis of AML cells by up-regulation of anti-apoptotic proteins

Konopleva

Konoplev²,

Hu³

et al. 2002

Leukemia

356

290

View full text Add to dashboard Cite

The aim of this study was to study interactions between stromal bone marrow microenvironment and leukemic cells. We tested the hypothesis that stromal cells prevent apoptosis of AML cells by up-regulating anti-apoptotic proteins in leukemic blasts. In HL-60 and NB-4 cells, serum deprivation-and ara-Cinduced apoptosis was diminished when cells were cocultured with murine MS-5 stromal cells (P Ͻ 0.02). This effect was reproduced with conditioned medium from MS-5 cells. Cocultivation with stromal cells induced Bcl-2 expression levels, both by PCR analysis and flow cytometry. In primary AML (n = 14), ara-C-induced apoptosis was significantly lower in cells cocultured with MS-5 cells than in controls (P Ͻ 0.001). This effect was partially preserved when leukemic cells were separated from stromal cells by a microporous insert (in 5/9 samples, P = 0.04). In addition, Bcl-2 levels were significantly higher in stroma-supported than in control CD34+ AML cells (P Ͻ 0.01). Bcl-X L levels were higher in 5/7 samples grown on stromal layers. Of note, in AML patients resistant to induction chemotherapy (n = 6), Bcl-2 increased significantly after cultivation with stromal cells, but no such increase was noted in cells from chemotherapy-sensitive patients. In conclusion, MS-5 stromal cells prevented apoptosis in HL-60 cells and in primary AML blasts via modulation of Bcl-2 family proteins. The observed association of high Bcl-2 expression in stroma-supported AML blasts in vitro with resistance to chemotherapy in vivo suggests that the same mechanisms may be operational in vivo.

show abstract

Section: Figurementioning

confidence: 99%

Stromal cells prevent apoptosis of AML cells by up-regulation of anti-apoptotic proteins

Konopleva

Konoplev²,

Hu³

et al. 2002

Leukemia

356

290

View full text Add to dashboard Cite

show abstract

“…Plasmin can also release other direct or indirect modulators of angiogenesis from the extracellular matrix, such as basic fibroblast growth factor, 40 or from cell surface receptors, like TGF-␤1. 41 In addition to releasing angiogenic growth factors from the extracellular matrix, plasmin also proteolytically activates 2 precursor forms of growth factors to the active state, HGF 42 and TGF-␤1. 43 As an example of the reciprocal cooperation between growth factors and plasmin formation in angiogenesis, VEGF, 44 basic fibroblast growth factor, 45 and angiogenin 46 induce plasminogen activator expression and enhance pericellular plasmin generation by endothelial cells.…”

Section: Walter and Sane Angiostatin Binds To Smcs 2045mentioning

confidence: 99%

Angiostatin Binds to Smooth Muscle Cells in the Coronary Artery and Inhibits Smooth Muscle Cell Proliferation and Migration In Vitro

Walter

Sane

1999

ATVB

View full text Add to dashboard Cite

Abstract-Angiostatin is an inhibitor of angiogenesis that is known to reduce endothelial cell proliferation and consequently prevent the progression of tumor metastases. However, the modest effect of angiostatin on endothelial cell proliferation raises the possibility that angiostatin might exert its effects on other cells. To determine the cellular distribution of angiostatin binding in tissues with neovasculature (atherosclerotic coronary arteries), we developed a fusion protein consisting of placental alkaline phosphatase and the first 3 kringles of plasminogen. Angiostatin binding colocalized with smooth muscle cells and could be inhibited by a 50-fold molar excess of plasminogen and 10 mmol/L ⑀-amino-n-caproic acid. The fusion protein also bound to smooth muscle cells in culture. Angiostatin inhibited hepatocyte growth factor-induced proliferation and migration of smooth muscle cells, suggesting that they are a target for the antiangiogenic effect of angiostatin.

show abstract

“…However, additional data point to other functions. Notably, the T␤RIII extracellular domain can be released from the cell surface as a soluble proteoglycan and is found in the extracellular matrix and serum (27). Soluble T␤RIII sequesters TGF␤ and inhibits its action in cell cultures, suggesting that the soluble form of T␤RIII may have opposing actions to those of its membrane-bound counterpart (3,31,56).…”

mentioning

confidence: 99%

Heart and Liver Defects and Reduced Transforming Growth Factor β2 Sensitivity in Transforming Growth Factor β Type III Receptor-Deficient Embryos

Stenvers

Tursky

Harder

et al. 2003

Molecular and Cellular Biology

222

175

View full text Add to dashboard Cite

The type III transforming growth factor ␤ (TGF␤) receptor (T␤RIII) binds both TGF␤ and inhibin with high affinity and modulates the association of these ligands with their signaling receptors. However, the significance of T␤RIII signaling in vivo is not known. In this study, we have sought to determine the role of T␤RIII during development. We identified the predominant expression sites of ⌻␤RIII mRNA as liver and heart during midgestation and have disrupted the murine T␤RIII gene by homologous recombination. Beginning at embryonic day 13.5, mice with mutations in ⌻␤RIII developed lethal proliferative defects in heart and apoptosis in liver, indicating that T␤RIII is required during murine somatic development. To assess the effects of the absence of T␤RIII on the function of its ligands, primary fibroblasts were generated from T␤RIII-null and wild-type embryos. Our results indicate that T␤RIII deficiency differentially affects the activities of TGF␤ ligands. Notably, T␤RIII-null cells exhibited significantly reduced sensitivity to TGF␤2 in terms of growth inhibition, reporter gene activation, and Smad2 nuclear localization, effects not observed with other ligands. These data indicate that T␤RIII is an important modulator of TGF␤2 function in embryonic fibroblasts and that reduced sensitivity to TGF␤2 may underlie aspects of the T␤RIII mutant phenotype.Members of the transforming growth factor ␤ (TGF␤) family are potent regulators of multiple cellular functions, including cell proliferation, differentiation, migration, and death (35, 64). As such, the TGF␤s are critical regulators of the growth and morphogenesis of a variety of tissues. Three TGF␤ isoforms (TGF␤1 to -3) have been described in mammals and are encoded by distinct genes (36). Although the three ligands have similar biological activities in many in vitro assays, null mutations in the three genes result in mice with distinct phenotypes, suggesting that each ligand has a unique role during murine somatic development (14,42,50). In mammalian cells, the diverse actions of the TGF␤s are mediated by two distinct type I and type II serine/threonine kinase receptors (T␤RI and T␤RII, respectively), which are expressed on most cell types and tissues (35). T␤RI and T␤RII can form a latent receptor complex, and ligand binding is required for the activation of the receptor complex (65). Upon TGF␤ binding, the receptors rotate relatively within the complex (65, 66), resulting in phosphorylation and activation of T␤RI by the constitutively active and autophosphorylated T␤RII (62). The activated T␤RI then directly signals to downstream intracellular substrates, e.g., Smads (21, 61).Many other cell surface receptors have been identified (64). Among them is the type III TGF␤ receptor T␤RIII, which binds to all three TGF␤s (32). In contrast to the type I and II receptors, T␤RIII, also known as betaglycan, appears dispensable for TGF␤-mediated signal transduction since most cells that lack functional T␤RIII still respond to TGF␤ (8). The murine form of T␤RIII is an 850-...

show abstract

Plasmin cleaves betaglycan and releases a 60 kDa transforming growth factor-β complex from the cell surface

Cited by 41 publications

References 35 publications

Stromal cells prevent apoptosis of AML cells by up-regulation of anti-apoptotic proteins

Stromal cells prevent apoptosis of AML cells by up-regulation of anti-apoptotic proteins

Angiostatin Binds to Smooth Muscle Cells in the Coronary Artery and Inhibits Smooth Muscle Cell Proliferation and Migration In Vitro

Heart and Liver Defects and Reduced Transforming Growth Factor β2 Sensitivity in Transforming Growth Factor β Type III Receptor-Deficient Embryos

Contact Info

Product

Resources

About