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Endostatin-induced ...
Endostatin-induced tyrosine kinase signaling through the Shb adaptor protein regulates endothelial cell apoptosis
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- Dixelius, Johan (author)
- Uppsala universitet,Cancer och vaskulärbiologi
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- Larsson, Helena (author)
- Uppsala universitet,Cancer och vaskulärbiologi
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Sasaki, Takako (author)
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- Holmqvist, Kristina (author)
- Uppsala universitet,Institutionen för medicinsk cellbiologi
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- Lu, Lingge (author)
- Uppsala universitet,Institutionen för medicinsk cellbiologi
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- Engström, Åke (author)
- Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi
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Timpl, Rupert (author)
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- Welsh, Michael (author)
- Uppsala universitet,Institutionen för medicinsk cellbiologi
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- Claesson-Welsh, Lena (author)
- Uppsala universitet,Cancer och vaskulärbiologi
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(creator_code:org_t)
- 2000
- 2000
- English.
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In: Blood. - 0006-4971 .- 1528-0020. ; 95:11, s. 3403-3411
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http://bloodjournal....
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https://urn.kb.se/re...
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Abstract
Subject headings
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- Endostatin, which corresponds to the C-terminal fragment of collagen XVIII, is a potent inhibitor of angiogenesis. Fibroblast growth factor-2 (FGF-2)-induced angiogenesis in the chicken chorioallantoic membrane was inhibited by endostatin, but not by an endostatin mutant R158/270A, lacking heparin-binding ability. Endostatin was internalized by endothelial cells, but not by mouse fibroblasts. Treatment of murine brain endothelial (IBE) cells with endostatin reduced the proportion of cells in S phase, whereas growth-arrested IBE cells in collagen gels treated with endostatin displayed enhanced tubular morphogenesis. IBE cells overexpressing Shb, an adaptor protein implicated in angiostatin-induced apoptosis, displayed elevated apoptosis and decreased tubular morphogenesis in collagen gels in response to endostatin when added together with FGF-2. Induction of apoptosis was dependent on the heparin-binding ability of endostatin and the expression of Shb with a functional Src homology 2 (SH2)-domain. Endostatin treatment for 10 minutes or 24 hours induced tyrosine phosphorylation of Shb and formation of multiprotein complexes. An Shb SH2 domain fusion protein precipitated a 125-kd phosphotyrosyl protein in endostatin-treated cells. The 125-kd component either contained intrinsic tyrosine kinase activity or occurred in complex with a tyrosine kinase. In conclusion, our data show that endostatin induces tyrosine kinase activity and enhanced apoptosis in FGF-treated endothelial cells.
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- art (subject category)
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