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Review
. 2014 Feb;1838(2):579-88.
doi: 10.1016/j.bbamem.2013.07.017. Epub 2013 Jul 24.

Mechanisms of talin-dependent integrin signaling and crosstalk

Mitali Das #  1 , Sujay Ithychanda #  1 , Jun Qin  1 , Edward F Plow  1
Affiliations
Review

Mechanisms of talin-dependent integrin signaling and crosstalk

Mitali Das et al. Biochim Biophys Acta. 2014 Feb.

Abstract

Cells undergo dynamic remodeling of the cytoskeleton during adhesion and migration on various extracellular matrix (ECM) substrates in response to physiological and pathological cues. The major mediators of such cellular responses are the heterodimeric adhesion receptors, the integrins. Extracellular or intracellular signals emanating from different signaling cascades cause inside-out signaling of integrins via talin, a cystokeletal protein that links integrins to the actin cytoskeleton. Various integrin subfamilies communicate with each other and growth factor receptors under diverse cellular contexts to facilitate or inhibit various integrin-mediated functions. Since talin is an essential mediator of integrin activation, much of the integrin crosstalk would therefore be influenced by talin. However, despite the existence of an extensive body of knowledge on the role of talin in integrin activation and as a stabilizer of ECM-actin linkage, information on its role in regulating inter-integrin communication is limited. This review will focus on the structure of talin, its regulation of integrin activation and discuss its potential role in integrin crosstalk. This article is part of a Special Issue entitled: Reciprocal influences between cell cytoskeleton and membrane channels, receptors and transporters. Guest Editor: Jean Claude Hervé.

Keywords: Actin; Crosstalk; Integrin; Talin.

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Figures

Fig1
Fig1. Bidirectional signaling across integrins
Agonist stimulation, signaling via G protein coupled receptors (GPCRs) and/or growth factor receptors can lead to “inside-out” signaling of integrins. Extracellular domains of resting integrins open up to bind extracellular matrix ligands (L). This leads to “outside-in” signaling of integrins resulting in cytoskeletal remodeling and downstream signaling cascades.
Fig 2
Fig 2. Structure of talin
Talin can be subdivided into head (talin-H) and rod (talin-R) regions. Talin-H is comprised of F0, F1, F2 and F3 domains while the talin-R has ~11 vinculin- and 3 actin-binding sites (in blue). The vinculin binding sites are dormant (in green) and are likely mechanoactivated (in red). PIP2, PKC, Rap1 and or RIAM can relieve the autoinhibitory effect of talin-R (1654-2344aa; black region) on F3 domain, promoting talin binding to β CT. The secondary integrin binding site is in orange.
Fig 3
Fig 3. Regions on different β integrin CTs to which talin has been reported to bind
Talin binds to the conserved membrane proximal region and the first NPxY/F motif (shown in red) on β CTs, as shown by the regions in brackets. However, the talin binding region may well extend to residues beyond these highlighted regions on the β CT. The second NPxY/F motif is shown in orange.
Fig 4
Fig 4. Model of talin mediated integrin crosstalk
(1) Agonists, extracellular or intracellular signals lead to unraveling of the autoinhibited talin by PIP2, RIAM, Rap1 or PKC. (2) Unmasked talin-F3 binds to and activates β integrin CT. (3) Engagement of multivalent ECM ligands via clustered and activated integrins can lead to sequestration of talin, thereby inhibiting other integrin species. Concomitant signaling via PKC or PKA may also contribute to transdominant inhibition of integrins or perpetuation of integrin activation via talin.
Fig 5
Fig 5. Crosstalk between talin and kindlin in displacement model of integrin activation
(1) In the first step, filamin bound to resting integrins can be displaced from β CT by migfilin, possibly recruited by kindlins to the vicinity of integrin tails. (2) This makes integrin β CT available for binding by talin at the proximal NPxY/F motif, which unclasps the integrins. 3) Kindlin binding converts the early stage of activated integrin to a high affinity state, allowing ligand binding. 4) Cooperative talin and kindlin binding to β CT may lead to crosstalk between integrins leading to clustered integrins and outside-in-signaling. It is still not clear if migfilin remains associated with kindlin after kindlin-β CT engagement and what are the events that trigger dissociation of migfilin-filamin contacts during this process.
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