Thrombospondin-1 signaling
Thrombospondin-1 is a large glycoprotein that is
synthesized and secreted by many cell types in response to injury and certain growth
factors. Thrombospondin-1 binds its receptor
CD36 and activates it. Activated
CD36 associates with Fyn and
stimulates its activity. Thrombospondin-1 signaling through
the CD36/ Fyn pathway leads to
activation of Mitogen-activated protein kinase p38 (p38MAPK)
via an unknown mechanism. p38MAPK activates by
phosphorylation Caspase-8, which in turn cleaves and
activates Caspase-3. Caspase-3
activation provides the cell with an apoptotic signal and therefore leads to inhibition
of angiogenesis [1], [2].
Thrombospondin -1 regulates
NO/ cGMP signaling acting
through both CD36 and CD47.
Thrombospondin-1 binding to
CD36 inhibits uptake of Myristic
acid [3]. Myristic acid
stimulates Endothelial nitric oxide synthase (eNOS)
activity, augmenting NO production [4]. NO in turn activates Soluble
guanylate cyclases, among them Guanylate cyclase 1, soluble.
Guanylate cyclases are enzymes catalyzing cGMP production.
cGMP is involved in regulation of proangiogenic responses.
cGMP also regulates smooth muscle contraction through a
Protein kinase, cGMP-dependent, type I (Protein kinase G1)/
Protein phosphatase 1, regulatory subunit 12A (MLCP (reg))/
Protein phosphatase 1, catalytic subunit, beta isoform (MLCP
(cat)) pathway. Thrombospondin-1 binding to
CD47 disrupts cGMP signaling,
apparently at the level of Guanylate cyclase 1, soluble.
Thus Thrombospondin-1 binding to
CD36 and CD47 leads to
inhibition of angiogenesis and vascular smooth muscle cell contraction [5], [6], [7].
In addition Thrombospondin-1 inhibits angiogenesis by
activation of Very low density lipoprotein receptor (VLDLR)
[8] and by inhibition of Fibroblast growth factor 2
(FGF2) and Vascular endothelial growth factor A
(VEGF-A) signaling, acting as a scavenger for the latter two
[9], [10].
Thrombospondin-1 binds to and activates latent
Transforming growth factor, beta 1 (TGF-beta 1) [11]. This interaction may play a role in TGF-beta 1
regulation of fibrosis development [12], [13], [14]
and wound healing [15].
Despite its generally inhibitory role in angiogenesis,
Thrombospondin-1 can exert proangiogenic activities under
specific conditions. Stimulation of angiogenesis by
Thrombospondin-1 occurs through its binding to
alpha-3/beta-1 integrin [16],
alpha-4/beta-1 integrin [17] and
alpha-9/beta-1 integrin [18].
References:
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Signals leading to apoptosis-dependent inhibition of neovascularization by thrombospondin-1.
Nature medicine 2000 Jan;6(1):41-8
- Anderson JC, Grammer JR, Wang W, Nabors LB, Henkin J, Stewart JE Jr, Gladson CL
ABT-510, a modified type 1 repeat peptide of thrombospondin, inhibits malignant glioma growth in vivo by inhibiting angiogenesis.
Cancer biology & therapy 2007 Mar;6(3):454-62
- Isenberg JS, Jia Y, Fukuyama J, Switzer CH, Wink DA, Roberts DD
Thrombospondin-1 inhibits nitric oxide signaling via CD36 by inhibiting myristic acid uptake.
The Journal of biological chemistry 2007 May 25;282(21):15404-15
- Zhu W, Smart EJ
Myristic acid stimulates endothelial nitric-oxide synthase in a CD36- and an AMP kinase-dependent manner.
The Journal of biological chemistry 2005 Aug 19;280(33):29543-50
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Thrombospondin-1 limits ischemic tissue survival by inhibiting nitric oxide-mediated vascular smooth muscle relaxation.
Blood 2007 Mar 1;109(5):1945-52
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Thrombospondin-1: a physiological regulator of nitric oxide signaling.
Cellular and molecular life sciences : CMLS 2008 Mar;65(5):728-42
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Regulation of nitric oxide signalling by thrombospondin 1: implications for anti-angiogenic therapies.
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Thrombospondins use the VLDL receptor and a nonapoptotic pathway to inhibit cell division in microvascular endothelial cells.
Molecular biology of the cell 2008 Feb;19(2):563-71
- Margosio B, Marchetti D, Vergani V, Giavazzi R, Rusnati M, Presta M, Taraboletti G
Thrombospondin 1 as a scavenger for matrix-associated fibroblast growth factor 2.
Blood 2003 Dec 15;102(13):4399-406
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Fibroblast growth factor-2 binding to the thrombospondin-1 type III repeats, a novel antiangiogenic domain.
The international journal of biochemistry & cell biology 2008;40(4):700-9
- Ribeiro SM, Poczatek M, Schultz-Cherry S, Villain M, Murphy-Ullrich JE
The activation sequence of thrombospondin-1 interacts with the latency-associated peptide to regulate activation of latent transforming growth factor-beta.
The Journal of biological chemistry 1999 May 7;274(19):13586-93
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Antisense oligonucleotides against thrombospondin-1 inhibit activation of tgf-beta in fibrotic renal disease in the rat in vivo.
The American journal of pathology 2003 Sep;163(3):1185-92
- Breitkopf K, Sawitza I, Westhoff JH, Wickert L, Dooley S, Gressner AM
Thrombospondin 1 acts as a strong promoter of transforming growth factor beta effects via two distinct mechanisms in hepatic stellate cells.
Gut 2005 May;54(5):673-81
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A thrombospondin-1 antagonist of transforming growth factor-beta activation blocks cardiomyopathy in rats with diabetes and elevated angiotensin II.
The American journal of pathology 2007 Sep;171(3):777-89
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Activation of latent TGF-beta by thrombospondin-1: mechanisms and physiology.
Cytokine & growth factor reviews 2000 Mar-Jun;11(1-2):59-69
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Cell contact-dependent activation of alpha3beta1 integrin modulates endothelial cell responses to thrombospondin-1.
Molecular biology of the cell 2000 Sep;11(9):2885-900
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Alpha4beta1 integrin mediates selective endothelial cell responses to thrombospondins 1 and 2 in vitro and modulates angiogenesis in vivo.
Circulation research 2004 Mar 5;94(4):462-70
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Interaction of alpha9beta1 integrin with thrombospondin-1 promotes angiogenesis.
Circulation research 2007 May 11;100(9):1308-16