Integrin Activation

Overview

Journal Biochem Soc Trans

Specialty Biochemistry

Date 2008 Mar 28

PMID 18363565

Citations 55

Authors

Asoka Banno

Mark H Ginsberg

Affiliations

Soon will be listed here.

Abstract

Agonist stimulation of integrin receptors, composed of transmembrane alpha and beta subunits, leads cells to regulate integrin affinity ('activation'), a process that controls cell adhesion and migration, and extracellular matrix assembly. A final step in integrin activation is the binding of talin to integrin beta cytoplasmic domains. We used forward, reverse and synthetic genetics to engineer and order integrin activation pathways of a prototypic integrin, platelet alphaIIbbeta3. PMA activated alphaIIbbeta3 only after expression of both PKCalpha (protein kinase Calpha) and talin at levels approximating those in platelets. Inhibition of Rap1 GTPase reduced alphaIIbbeta3 activation, whereas expression of constitutively active Rap1A(G12V) bypassed the requirement for PKCalpha. Overexpression of a Rap effector, RIAM (Rap1-GTP-interacting adaptor molecule), activated alphaIIbbeta3 and bypassed the requirement for PKCalpha and Rap1. In addition, shRNA (short hairpin RNA)-mediated knockdown of RIAM blocked talin interaction with and activation of integrin alphaIIbbeta3. Rap1 activation caused the formation of an 'activation complex' containing talin and RIAM that redistributed to the plasma membrane and activated alphaIIbbeta3. The central finding was that this Rap1-induced formation of an 'integrin activation complex' leads to the unmasking of the integrin-binding site on talin, resulting in integrin activation.

Citing Articles

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References

Gottschalk K, Adams P, Brunger A, Kessler H . Transmembrane signal transduction of the alpha(IIb)beta(3) integrin. Protein Sci. 2002; 11(7):1800-12. PMC: 2373644. DOI: 10.1110/ps.4120102. View

Tang P, Cao C, Xu M, Zhang L . Cytoskeletal protein radixin activates integrin alpha(M)beta(2) by binding to its cytoplasmic tail. FEBS Lett. 2007; 581(6):1103-8. DOI: 10.1016/j.febslet.2007.02.013. View

Arnaout M, Mahalingam B, Xiong J . Integrin structure, allostery, and bidirectional signaling. Annu Rev Cell Dev Biol. 2005; 21:381-410. DOI: 10.1146/annurev.cellbio.21.090704.151217. View

Stefansson A, Armulik A, Nilsson I, von Heijne G, Johansson S . Determination of N- and C-terminal borders of the transmembrane domain of integrin subunits. J Biol Chem. 2004; 279(20):21200-5. DOI: 10.1074/jbc.M400771200. View

Jin M, Andricioaei I, Springer T . Conversion between three conformational states of integrin I domains with a C-terminal pull spring studied with molecular dynamics. Structure. 2004; 12(12):2137-47. DOI: 10.1016/j.str.2004.10.005. View

Humphries M, McEwan P, Barton S, Buckley P, Bella J, Mould A . Integrin structure: heady advances in ligand binding, but activation still makes the knees wobble. Trends Biochem Sci. 2003; 28(6):313-20. DOI: 10.1016/s0968-0004(03)00112-9. View

Takagi J, Petre B, Walz T, Springer T . Global conformational rearrangements in integrin extracellular domains in outside-in and inside-out signaling. Cell. 2002; 110(5):599-11. DOI: 10.1016/s0092-8674(02)00935-2. View

Franco S, Rodgers M, Perrin B, Han J, Bennin D, Critchley D . Calpain-mediated proteolysis of talin regulates adhesion dynamics. Nat Cell Biol. 2004; 6(10):977-83. DOI: 10.1038/ncb1175. View

OToole T, Mandelman D, Forsyth J, Shattil S, Plow E, Ginsberg M . Modulation of the affinity of integrin alpha IIb beta 3 (GPIIb-IIIa) by the cytoplasmic domain of alpha IIb. Science. 1991; 254(5033):845-7. DOI: 10.1126/science.1948065. View

10.

Qin J, Vinogradova O, Plow E . Integrin bidirectional signaling: a molecular view. PLoS Biol. 2004; 2(6):e169. PMC: 423143. DOI: 10.1371/journal.pbio.0020169. View

11.

Nishida N, Xie C, Shimaoka M, Cheng Y, Walz T, Springer T . Activation of leukocyte beta2 integrins by conversion from bent to extended conformations. Immunity. 2006; 25(4):583-94. DOI: 10.1016/j.immuni.2006.07.016. View

12.

Luo B, Carman C, Takagi J, Springer T . Disrupting integrin transmembrane domain heterodimerization increases ligand binding affinity, not valency or clustering. Proc Natl Acad Sci U S A. 2005; 102(10):3679-84. PMC: 553322. DOI: 10.1073/pnas.0409440102. View

13.

Critchley D . Focal adhesions - the cytoskeletal connection. Curr Opin Cell Biol. 2000; 12(1):133-9. DOI: 10.1016/s0955-0674(99)00067-8. View

14.

Calderwood D . Integrin activation. J Cell Sci. 2004; 117(Pt 5):657-66. DOI: 10.1242/jcs.01014. View

15.

Katagiri K, Hattori M, Minato N, Irie S, Takatsu K, Kinashi T . Rap1 is a potent activation signal for leukocyte function-associated antigen 1 distinct from protein kinase C and phosphatidylinositol-3-OH kinase. Mol Cell Biol. 2000; 20(6):1956-69. PMC: 110813. DOI: 10.1128/MCB.20.6.1956-1969.2000. View

16.

Adair B, Xiong J, Maddock C, Goodman S, Arnaout M, Yeager M . Three-dimensional EM structure of the ectodomain of integrin {alpha}V{beta}3 in a complex with fibronectin. J Cell Biol. 2005; 168(7):1109-18. PMC: 2171847. DOI: 10.1083/jcb.200410068. View

17.

Takagi J, Erickson H, Springer T . C-terminal opening mimics 'inside-out' activation of integrin alpha5beta1. Nat Struct Biol. 2001; 8(5):412-6. DOI: 10.1038/87569. View

18.

van der Flier A, Sonnenberg A . Function and interactions of integrins. Cell Tissue Res. 2001; 305(3):285-98. DOI: 10.1007/s004410100417. View

19.

Ma Y, Yang J, Pesho M, Vinogradova O, Qin J, Plow E . Regulation of integrin alphaIIbbeta3 activation by distinct regions of its cytoplasmic tails. Biochemistry. 2006; 45(21):6656-62. DOI: 10.1021/bi060279h. View

20.

Rees D, Ades S, Singer S, Hynes R . Sequence and domain structure of talin. Nature. 1990; 347(6294):685-9. DOI: 10.1038/347685a0. View