title: A dual role for integrin-linked kinase in platelets: regulating integrin function and alpha-granule secretion.
abstract: 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.
authors.affiliation: Institute of Cardiovascular and Metabolic Research and School of Biological Sciences, University of Reading, Reading, United Kingdom.
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Tucker
authors.forename: Tanya
authors.initials: T
authors.lastname: Sage
authors.forename: Joanne M
authors.initials: JM
authors.lastname: Stevens
authors.forename: Peter A
authors.initials: PA
authors.lastname: Jordan
authors.forename: Sarah
authors.initials: S
authors.lastname: Jones
authors.forename: Natasha E
authors.initials: NE
authors.lastname: Barrett
authors.forename: Rene
authors.initials: R
authors.lastname: St-Arnaud
authors.forename: Jonathan
authors.initials: J
authors.lastname: Frampton
authors.forename: Shoukat
authors.initials: S
authors.lastname: Dedhar
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Gibbins
mesh_terms: 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
chemical_list: D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D017346:Protein Serine-Threonine Kinases; D000099200:Scaffold Protein ILK
references.citation: Genes Dev. 2003 Apr 1;17(7):926-40
references.pmid: 12670870
references.citation: J Neurosci. 2006 Dec 20;26(51):13344-56
references.pmid: 17182785
references.citation: Nat Rev Mol Cell Biol. 2006 Jan;7(1):20-31
references.pmid: 16493410
references.citation: J Biol Chem. 2001 Jul 20;276(29):27462-9
references.pmid: 11313365
references.citation: Genes Dev. 2006 Sep 1;20(17):2355-60
references.pmid: 16951252
references.citation: J Biol Chem. 1998 Jun 12;273(24):14827-37
references.pmid: 9614084
references.citation: J Mol Biol. 1984 Sep 15;178(2):481-6
references.pmid: 6333513
references.citation: Oncogene. 1999 Dec 23;18(56):8024-32
references.pmid: 10637513
references.citation: Biochem Biophys Res Commun. 2007 Feb 16;353(3):638-43
references.pmid: 17194454
references.citation: FASEB J. 1995 May;9(8):576-96
references.pmid: 7768349
references.citation: Genes Dev. 2006 Sep 1;20(17):2361-72
references.pmid: 16921028
references.citation: J Cell Biol. 2008 Mar 10;180(5):1037-49
references.pmid: 18332223
references.citation: J Cell Sci. 1999 Dec;112 ( Pt 24):4589-99
references.pmid: 10574708
references.citation: Oncogene. 2000 Aug 3;19(33):3811-5
references.pmid: 10949937
references.citation: EMBO Rep. 2003 Apr;4(4):432-8
references.pmid: 12671688
references.citation: J Biol Chem. 2002 Oct 11;277(41):38328-38
references.pmid: 12167643
references.citation: Blood. 2002 Jan 1;99(1):137-44
references.pmid: 11756163
references.citation: J Clin Invest. 1999 Mar;103(6):879-87
references.pmid: 10079109
references.citation: Methods Mol Biol. 2004;272:165-86
references.pmid: 15226544
references.citation: J Biol Chem. 2002 Jan 4;277(1):318-26
references.pmid: 11694512
references.citation: J Exp Med. 2007 Dec 24;204(13):3103-11
references.pmid: 18086863
references.citation: J Biol Chem. 2004 Oct 1;279(40):41695-705
references.pmid: 15284246
references.citation: Biochem Biophys Res Commun. 2002 Oct 11;297(5):1324-31
references.pmid: 12372433
references.citation: Lab Invest. 2005 Nov;85(11):1342-56
references.pmid: 16170337
references.citation: Eur J Cell Biol. 2006 Apr;85(3-4):255-63
references.pmid: 16546570
references.citation: J Cell Sci. 2002 Dec 15;115(Pt 24):4777-86
references.pmid: 12432066
references.citation: Circulation. 2006 Nov 21;114(21):2271-9
references.pmid: 17088456
references.citation: Methods Mol Biol. 2004;272:47-63
references.pmid: 15226533
references.citation: Cancer Metastasis Rev. 2003 Dec;22(4):375-84
references.pmid: 12884912
references.citation: J Thromb Haemost. 2004 Aug;2(8):1443-52
references.pmid: 15304053
references.citation: EMBO J. 2001 May 1;20(9):2160-70
references.pmid: 11331582
references.citation: Br J Cancer. 2003 Jun 2;88(11):1755-62
references.pmid: 12771992
references.citation: Nat Med. 2008 Mar;14(3):325-30
references.pmid: 18278053
references.citation: Science. 1999 Aug 13;285(5430):1028-32
references.pmid: 10446041
references.citation: Proc Natl Acad Sci U S A. 1998 Sep 15;95(19):11211-6
references.pmid: 9736715
references.citation: Thromb Haemost. 2002 Jul;88(1):115-22
references.pmid: 12152651
references.citation: Thromb Haemost. 2001 Jul;86(1):214-21
references.pmid: 11487009
references.citation: Blood. 2005 May 15;105(10):3879-87
references.pmid: 15671445
references.citation: J Cell Biol. 2001 Mar 5;152(5):1007-18
references.pmid: 11238456
references.citation: Nature. 1996 Jan 4;379(6560):91-6
references.pmid: 8538749
references.citation: Curr Opin Cell Biol. 2005 Oct;17(5):509-16
references.pmid: 16099636
references.citation: J Biol Chem. 1998 Dec 18;273(51):34437-43
references.pmid: 9852111
references.citation: J Cell Biol. 2003 Jul 7;162(1):139-48
references.pmid: 12835312
references.citation: Biochem J. 1995 Mar 1;306 ( Pt 2):337-44
references.pmid: 7534064
references.citation: Mol Cell Biol. 1999 Mar;19(3):2425-34
references.pmid: 10022929
references.citation: Proc Natl Acad Sci U S A. 2003 Feb 4;100(3):992-7
references.pmid: 12552125
references.citation: Orphanet J Rare Dis. 2006 Apr 06;1:10
references.pmid: 16722529
references.citation: Mol Cell Biol. 2004 Sep;24(18):8134-44
references.pmid: 15340074
references.citation: J Biol Chem. 2003 Jun 20;278(25):22374-8
references.pmid: 12686550
references.citation: J Cell Sci. 2004 Jul 15;117(Pt 16):3415-25
references.pmid: 15252124
references.citation: Blood. 2004 Sep 15;104(6):1606-15
references.pmid: 15205259
references.citation: J Cell Biol. 2001 Nov 12;155(4):505-10
references.pmid: 11696562