Development - Thrombospondin-1 signaling

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:

1. Jiménez B, Volpert OV, Crawford SE, Febbraio M, Silverstein RL, Bouck N
   Signals leading to apoptosis-dependent inhibition of neovascularization by thrombospondin-1. Nature medicine 2000 Jan;6(1):41-8
2. 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
3. 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
4. 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
5. Isenberg JS, Hyodo F, Matsumoto K, Romeo MJ, Abu-Asab M, Tsokos M, Kuppusamy P, Wink DA, Krishna MC, Roberts DD
   Thrombospondin-1 limits ischemic tissue survival by inhibiting nitric oxide-mediated vascular smooth muscle relaxation. Blood 2007 Mar 1;109(5):1945-52
6. Isenberg JS, Frazier WA, Roberts DD
   Thrombospondin-1: a physiological regulator of nitric oxide signaling. Cellular and molecular life sciences : CMLS 2008 Mar;65(5):728-42
7. Isenberg JS, Martin-Manso G, Maxhimer JB, Roberts DD
   Regulation of nitric oxide signalling by thrombospondin 1: implications for anti-angiogenic therapies. Nature reviews. Cancer 2009 Mar;9(3):182-94
8. Oganesian A, Armstrong LC, Migliorini MM, Strickland DK, Bornstein P
   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
9. 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
10. Margosio B, Rusnati M, Bonezzi K, Cordes BL, Annis DS, Urbinati C, Giavazzi R, Presta M, Ribatti D, Mosher DF, Taraboletti G
    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
11. 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
12. Daniel C, Takabatake Y, Mizui M, Isaka Y, Kawashi H, Rupprecht H, Imai E, Hugo C
    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
13. 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
14. Belmadani S, Bernal J, Wei CC, Pallero MA, Dell'italia L, Murphy-Ullrich JE, Berecek KH
    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
15. Murphy-Ullrich JE, Poczatek M
    Activation of latent TGF-beta by thrombospondin-1: mechanisms and physiology. Cytokine & growth factor reviews 2000 Mar-Jun;11(1-2):59-69
16. Chandrasekaran L, He CZ, Al-Barazi H, Krutzsch HC, Iruela-Arispe ML, Roberts DD
    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
17. Calzada MJ, Zhou L, Sipes JM, Zhang J, Krutzsch HC, Iruela-Arispe ML, Annis DS, Mosher DF, Roberts DD
    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
18. Staniszewska I, Zaveri S, Del Valle L, Oliva I, Rothman VL, Croul SE, Roberts DD, Mosher DF, Tuszynski GP, Marcinkiewicz C
    Interaction of alpha9beta1 integrin with thrombospondin-1 promotes angiogenesis. Circulation research 2007 May 11;100(9):1308-16