A dual role for integrin-linked kinase in platelets: regulating integrin function and alpha-granule secretion.
Integrin-linked kinase (ILK) has been implicated in the regulation of a range of fundamental biological processes such as cell survival, growth, differentiation, and adhesion. In platelets ILK associates with beta1- and beta3-containing integrins, which are of paramount importance for the function of platelets. Upon stimulation of platelets this association with the integrins is increased and ILK kinase activity is up-regulated, suggesting that ILK may be important for the coordination of platelet responses. In this study a conditional knockout mouse model was developed to examine the role of ILK in platelets. The ILK-deficient mice showed an increased bleeding time and volume, and despite normal ultrastructure the function of ILK-deficient platelets was decreased significantly. This included reduced aggregation, fibrinogen binding, and thrombus formation under arterial flow conditions. Furthermore, although early collagen stimulated signaling such as PLCgamma2 phosphorylation and calcium mobilization were unaffected in ILK-deficient platelets, a selective defect in alpha-granule, but not dense-granule, secretion was observed. These results indicate that as well as involvement in the control of integrin affinity, ILK is required for alpha-granule secretion and therefore may play a central role in the regulation of platelet function.
Tucker
Katherine L
KL
Institute of Cardiovascular and Metabolic Research and School of Biological Sciences, University of Reading, Reading, United Kingdom.
Sage
Tanya
T
Stevens
Joanne M
JM
Jordan
Peter A
PA
Jones
Sarah
S
Barrett
Natasha E
NE
St-Arnaud
Rene
R
Frampton
Jonathan
J
Dedhar
Shoukat
S
Gibbins
Jonathan M
JM
D000818:Animals; D001792:Blood Platelets / Q000201:enzymology* / Q000378:metabolism; D003001:Cloning, Molecular; D006470:Hemorrhage / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015539:Platelet Activation / Q000235:genetics*; D010974:Platelet Aggregation / Q000235:genetics; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D022142:Secretory Vesicles / Q000378:metabolism*; D013927:Thrombosis / Q000235:genetics; D000099200:Scaffold Protein ILK
D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D017346:Protein Serine-Threonine Kinases; D000099200:Scaffold Protein ILK
Genes Dev. 2003 Apr 1;17(7):926-40
12670870
J Neurosci. 2006 Dec 20;26(51):13344-56
17182785
Nat Rev Mol Cell Biol. 2006 Jan;7(1):20-31
16493410
J Biol Chem. 2001 Jul 20;276(29):27462-9
11313365
Genes Dev. 2006 Sep 1;20(17):2355-60
16951252
J Biol Chem. 1998 Jun 12;273(24):14827-37
9614084
J Mol Biol. 1984 Sep 15;178(2):481-6
6333513
Oncogene. 1999 Dec 23;18(56):8024-32
10637513
Biochem Biophys Res Commun. 2007 Feb 16;353(3):638-43
17194454
FASEB J. 1995 May;9(8):576-96
7768349
Genes Dev. 2006 Sep 1;20(17):2361-72
16921028
J Cell Biol. 2008 Mar 10;180(5):1037-49
18332223
J Cell Sci. 1999 Dec;112 ( Pt 24):4589-99
10574708
Oncogene. 2000 Aug 3;19(33):3811-5
10949937
EMBO Rep. 2003 Apr;4(4):432-8
12671688
J Biol Chem. 2002 Oct 11;277(41):38328-38
12167643
Blood. 2002 Jan 1;99(1):137-44
11756163
J Clin Invest. 1999 Mar;103(6):879-87
10079109
Methods Mol Biol. 2004;272:165-86
15226544
J Biol Chem. 2002 Jan 4;277(1):318-26
11694512
J Exp Med. 2007 Dec 24;204(13):3103-11
18086863
J Biol Chem. 2004 Oct 1;279(40):41695-705
15284246
Biochem Biophys Res Commun. 2002 Oct 11;297(5):1324-31
12372433
Lab Invest. 2005 Nov;85(11):1342-56
16170337
Eur J Cell Biol. 2006 Apr;85(3-4):255-63
16546570
J Cell Sci. 2002 Dec 15;115(Pt 24):4777-86
12432066
Circulation. 2006 Nov 21;114(21):2271-9
17088456
Methods Mol Biol. 2004;272:47-63
15226533
Cancer Metastasis Rev. 2003 Dec;22(4):375-84
12884912
J Thromb Haemost. 2004 Aug;2(8):1443-52
15304053
EMBO J. 2001 May 1;20(9):2160-70
11331582
Br J Cancer. 2003 Jun 2;88(11):1755-62
12771992
Nat Med. 2008 Mar;14(3):325-30
18278053
Science. 1999 Aug 13;285(5430):1028-32
10446041
Proc Natl Acad Sci U S A. 1998 Sep 15;95(19):11211-6
9736715
Thromb Haemost. 2002 Jul;88(1):115-22
12152651
Thromb Haemost. 2001 Jul;86(1):214-21
11487009
Blood. 2005 May 15;105(10):3879-87
15671445
J Cell Biol. 2001 Mar 5;152(5):1007-18
11238456
Nature. 1996 Jan 4;379(6560):91-6
8538749
Curr Opin Cell Biol. 2005 Oct;17(5):509-16
16099636
J Biol Chem. 1998 Dec 18;273(51):34437-43
9852111
J Cell Biol. 2003 Jul 7;162(1):139-48
12835312
Biochem J. 1995 Mar 1;306 ( Pt 2):337-44
7534064
Mol Cell Biol. 1999 Mar;19(3):2425-34
10022929
Proc Natl Acad Sci U S A. 2003 Feb 4;100(3):992-7
12552125
Orphanet J Rare Dis. 2006 Apr 06;1:10
16722529
Mol Cell Biol. 2004 Sep;24(18):8134-44
15340074
J Biol Chem. 2003 Jun 20;278(25):22374-8
12686550
J Cell Sci. 2004 Jul 15;117(Pt 16):3415-25
15252124
Blood. 2004 Sep 15;104(6):1606-15
15205259
J Cell Biol. 2001 Nov 12;155(4):505-10
11696562