Integrin signaling

Stable Identifier
R-HSA-354192
DOI
10.3180/REACT_15523.1
Type
Pathway
Species
Homo sapiens
ReviewStatus
5/5
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Integrin signaling
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Integrins are a major family of cell surface receptors that modulate cell adhesion, migration, proliferation and survival through interaction with the extracellular matrix (ECM) and the actin cytoskeleton. Integrins are type 1 transmembrane proteins that exist at the cell surface as heterodimers of alpha and beta subunits, of which there are 18 and 8 different isoforms, respectively, in human cells. In addition to their mechanical role in mediating contact between the ECM and the cytoskeleton, integrins also modulate intracellular signaling pathways governing cytoskeletal rearrangements and pro-survival and mitogenic signaling (reviewed in Hehlgans et al, 2007; Harburger and Calderwood, 2009; Ata and Antonescu, 2017).
In this pathway, we describe signaling through integrin alphaIIb beta3 as a representative example.
At the sites of vascular injury bioactive molecules such as thrombin, ADP, collagen, fibrinogen and thrombospondin are generated, secreted or exposed. These stimuli activate platelets, converting the major platelet integrin alphaIIbbeta3 from a resting state to an active conformation, in a process termed integrin priming or 'inside-out signalling'. Integrin activation refers to the change required to enhance ligand-binding activity. The activated alphaIIbbeta3 interacts with the fibrinogen and links platelets together in an aggregate to form a platelet plug. AlphaIIbbeta3 bound to fibrin generates more intracellular signals (outside-in signalling), causing further platelet activation and platelet-plug retraction.
In the resting state the alpha and beta tails are close together. This interaction keeps the membrane proximal regions in a bent conformation that maintains alphaIIbbeta3 in a low affinity state.
Integrin alphaIIbbeta3 is released from its inactive state by interaction with the protein talin. Talin interacts with the beta3 cytoplasmic domain and disrupts the salt bridge between the alpha and beta chains. This separation in the cytoplasmic regions triggers the conformational change in the extracellular domain that increases its affinity to fibrinogen.
Much of talin exists in an inactive cytosolic pool, and the Rap1 interacting adaptor molecule (RIAM) is implicated in talin activation and translocation to beta3 integrin cytoplasmic domain.
Literature References
PubMed ID Title Journal Year
16102042 GPVI and integrin alphaIIb beta3 signaling in platelets

Watson, SP, Auger, JM, McCarty, OJ, Pearce, AC

J Thromb Haemost 2005
10508650 Integrin alpha(IIb)beta(3) signaling in platelet adhesion and aggregation

Parise, LV

Curr Opin Cell Biol 1999
17084981 Signalling via integrins: implications for cell survival and anticancer strategies

Hehlgans, S, Haase, M, Cordes, N

Biochim Biophys Acta 2007
19118207 Integrin signalling at a glance

Harburger, DS, Calderwood, DA

J. Cell. Sci. 2009
28106780 Integrins and Cell Metabolism: An Intimate Relationship Impacting Cancer

Ata, R, Antonescu, CN

Int J Mol Sci 2017
14754902 Integrin activation

Calderwood, DA

J Cell Sci 2004
17624957 Platelet integrins and immunoreceptors

Kasirer-Friede, A, Kahn, ML, Shattil, SJ

Immunol Rev 2007
15205259 Integrins: dynamic scaffolds for adhesion and signaling in platelets

Shattil, SJ, Newman, PJ

Blood 2004
10605720 Signaling through platelet integrin alpha IIb beta 3: inside-out, outside-in, and sideways

Shattil, SJ

Thromb Haemost 1999
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Orthologous Events
Integrin signaling (Bos taurus)
Integrin signaling (Caenorhabditis elegans)
Integrin signaling (Canis familiaris)
Integrin signaling (Danio rerio)
Integrin signaling (Dictyostelium discoideum)
Integrin signaling (Drosophila melanogaster)
Integrin signaling (Gallus gallus)
Integrin signaling (Mus musculus)
Integrin signaling (Rattus norvegicus)
Integrin signaling (Saccharomyces cerevisiae)
Integrin signaling (Sus scrofa)
Integrin signaling (Xenopus tropicalis)
Cross References
BioModels Database
Authored
Garapati, P V  (2008-06-16)
Reviewed
Shattil, SJ  (2008-09-16)
Created
Garapati, P V  (2008-06-16)
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