Inhibition of endothelial cell migration by thrombospondin-1 type-1 repeats is mediated by beta1 integrins.
The anti-angiogenic effect of thrombospondin-1 has been shown to be mediated through binding of the type-1 repeat (TSR) domain to the CD36 transmembrane receptor. We now report that the TSR domain can inhibit VEGF-induced migration in human umbilical vein endothelial cells (HUVEC), cells that lack CD36. Moreover, we identified beta1 integrins as a critical receptor in TSR-mediated inhibition of migration in HUVEC. Using pharmacological inhibitors of downstream VEGF receptor effectors, we found that phosphoinositide 3-kinase (PI3k) was essential for TSR-mediated inhibition of HUVEC migration, but that neither PLCgamma nor Akt was necessary for this response. Furthermore, beta1 integrins were critical for TSR-mediated inhibition of microvascular endothelial cells, cells that express CD36. Together, our results indicate that beta1 integrins mediate the anti-migratory effects of TSR through a PI3k-dependent mechanism.
Short
Sarah M
SM
Vascular Biology Program, Children's Hospital, Boston, MA 02115, USA.
Derrien
Alexandrine
A
Narsimhan
Radha P
RP
Lawler
Jack
J
Ingber
Donald E
DE
Zetter
Bruce R
BR
D018955:CD36 Antigens / Q000378:metabolism; D002465:Cell Movement / Q000502:physiology*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051966:Phospholipase C gamma; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D019700:Thrombospondin 1 / Q000378:metabolism*; D010738:Type C Phospholipases / Q000378:metabolism; D014471:Umbilical Veins / Q000166:cytology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D018955:CD36 Antigens; D019012:Integrin beta1; D019869:Phosphatidylinositol 3-Kinases; D051966:Phospholipase C gamma; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D019700:Thrombospondin 1; D010738:Type C Phospholipases; D042461:Vascular Endothelial Growth Factor A; C494918:AKT1 protein, human
Growth Factors. 1996;13(1-2):57-64
8962720
J Cell Biol. 1996 Dec;135(6 Pt 1):1633-42
8978828
J Cell Biol. 1997 Aug 11;138(3):707-17
9245797
Cancer Res. 1998 Mar 15;58(6):1298-304
9515819
Curr Opin Cell Biol. 1998 Apr;10(2):220-31
9561846
Proc Natl Acad Sci U S A. 1998 May 26;95(11):6343-8
9600967
Mol Biol Cell. 1998 Aug;9(8):1969-80
9693360
J Biol Chem. 1998 Nov 13;273(46):30336-43
9804796
Microcirculation. 1998;5(4):239-57
9866115
Clin Immunol. 1999 Jan;90(1):10-4
9884347
Mol Pharmacol. 1999 Feb;55(2):332-8
9927626
J Biol Chem. 1999 Apr 9;274(15):10002-7
10187776
Eur J Immunol. 1999 May;29(5):1426-34
10359096
J Cell Biol. 1999 Aug 9;146(3):673-82
10444074
Circulation. 1999 Sep 28;100(13):1423-31
10500044
Exp Cell Res. 1999 Nov 1;252(2):262-72
10527617
Nat Med. 2000 Jan;6(1):41-8
10613822
Am J Pathol. 2000 Apr;156(4):1345-62
10751360
Clin Cancer Res. 2000 Jul;6(7):2941-50
10914744
FEBS Lett. 2000 Jul 21;477(3):258-62
10908731
Mol Biol Cell. 2000 Sep;11(9):2885-900
10982388
Matrix Biol. 2000 Dec;19(7):597-614
11102749
J Cell Biol. 2000 Dec 25;151(7):1549-60
11134082
Cardiovasc Res. 2001 Feb 16;49(3):568-81
11166270
Exp Cell Res. 2001 Feb 1;263(1):173-82
11161716
EMBO J. 2001 Mar 15;20(6):1232-44
11250890
J Cell Sci. 2001 Apr;114(Pt 8):1579-89
11282033
J Clin Invest. 2001 Apr;107(8):929-34
11306593
J Biol Chem. 2001 May 4;276(18):15240-8
11278365
Trends Immunol. 2001 Mar;22(3):129
11334027
J Biol Chem. 2001 Jul 20;276(29):26969-79
11350975
Mol Biol Cell. 2001 Oct;12(10):3126-38
11598197
Mol Cell Biochem. 2001 Aug;224(1-2):81-9
11693202
Cancer Res. 2001 Nov 1;61(21):7830-9
11691800
Prostate. 2001 Dec 1;49(4):293-305
11746276
Gen Pharmacol. 2000 Nov;35(5):227-31
11888677
J Cell Mol Med. 2002 Jan-Mar;6(1):1-12
12003665
Cancer Res. 2002 Oct 1;62(19):5580-9
12359771
J Cell Biol. 2002 Oct 28;159(2):373-82
12391027
Cancer Cell. 2003 Mar;3(3):219-31
12676581
Proc Natl Acad Sci U S A. 2003 Apr 15;100(8):4766-71
12682293
Cold Spring Harb Symp Quant Biol. 2002;67:143-53
12858535
Circ Res. 2004 Mar 5;94(4):462-70
14699013
J Biol Chem. 2004 Mar 12;279(11):10005-12
14699139
Int J Biochem Cell Biol. 2004 Jun;36(6):961-8
15094109
J Biol Chem. 2004 May 7;279(19):20178-85
14973128
Mol Biol Cell. 2004 Jun;15(6):2558-67
15034138
Oncologist. 2004;9 Suppl 1:2-10
15178810
Circ Res. 2004 Jun 11;94(11):1443-50
15192038
Surgery. 2004 Aug;136(2):143-9
15300173
J Biol Chem. 2004 Oct 1;279(40):41734-43
15292271
Nature. 1980 May 1;285(5759):41-3
6990271
Proc Natl Acad Sci U S A. 1990 May;87(9):3579-83
2333303
Proc Natl Acad Sci U S A. 1990 Sep;87(17):6624-8
1697685
Exp Cell Res. 1991 May;194(1):69-77
1707824
J Immunol. 1992 Jan 1;148(1):78-83
1370173
Biochem Biophys Res Commun. 1992 Feb 14;182(3):1208-17
1371676
Exp Cell Res. 1992 Jun;200(2):272-84
1374036
Exp Cell Res. 1993 Apr;205(2):232-9
8482334
Biochem Biophys Res Commun. 1993 Jun 15;193(2):571-8
7685596
J Cell Biol. 1993 Jul;122(2):497-511
7686555
J Cell Biochem. 1993 Sep;53(1):74-84
8227183
Mol Biol Cell. 1993 Sep;4(9):953-61
8257797
Science. 1994 Apr 22;264(5158):569-71
7512751
Microvasc Res. 1994 Jan;47(1):31-40
7517489
Nat Med. 1995 Jan;1(1):27-31
7584949
Science. 1995 Dec 1;270(5241):1500-2
7491498